Method and apparatus for dry granulation

ABSTRACT

The invention provides, inter alia, a method for producing granules from a powder, characterized in that compaction force is applied to the powder to produce a compacted mass comprising a mixture of fine particles and granules and separating and removing fine particles and/or small granules from the other granules by entraining the fine particles and/or small granules in a gas stream. Also provided are apparatus for use in the process and tablets formed by compression of the resultant granules.

This application is a continuation of U.S. application Ser. No.12/941,314 filed Nov. 8, 2010, which is a continuation of PCTInternational Application Number PCT/EP2009/055627 filed on May 8, 2009(which claims priority on Finnish Application No. 20080351 filed on May9, 2008), PCT International Application No. PCT/EP2009/055628) filed onMay 8, 2009 (which claims priority on Finnish Application No. 20080352filed on May 9, 2008), PCT International Application NumberPCT/EP2009/055629 filed on May 8, 2009 (which claims priority on FinnishApplication No. 20080353 filed on May 9, 2008), PCT InternationalApplication Number PCT/EP2009/055630 filed on May 8, 2009 (which claimspriority on Finnish Application No. 20080346 filed on May 9, 2008) andPCT International Application Number PCT/EP2009/055631 filed on May 8,2009 (which claims priority on Finnish Application No. 20080355 filed onMay 9, 2008). This application is also a continuation-in-part of U.S.application Ser. No. 12/580,558 filed Oct. 16, 2009, which is acontinuation of U.S. application Ser. No. 12/463,186, filed May 8, 2009,(which claims priority on Finnish Application Nos. 20080347 filed May 9,2008, 20080348 filed May 9, 2008, 20080349 filed May 9, 2008, 20080350filed May 9, 2008, 20080354 filed May 9, 2008, 20080356 filed May 9,2008 and 20080357 filed May 12, 2008), which is a continuation-in-partof U.S. application Ser. No. 11/979,530 filed Nov. 5, 2007 (which claimspriority on Finnish application nos. 20060990 filed Nov. 10, 2006,20061146 filed Dec. 21, 2006 and 20070521 filed Jul. 2, 2007). Theentire contents of all of the above applications are hereby incorporatedby reference in their entirety into the present application.

TECHNICAL FIELD OF INVENTION

The invention relates to method and apparatus for dry granulation.

BACKGROUND OF THE INVENTION

Tablets are one of the most frequently employed delivery forms for mostmedicinal preparations. This situation can be explained by the fact thatthis dosage form allows for accurate dosage of the active component ofthe medicinal formulation. Furthermore, handling and packaging areeasier and shelf life and stability of these preparations are generallybetter than those of other formulations.

These same arguments also explain the reason why tablets are often usedas media for other applications such as food, including confectioneryproducts, aromas or sweeteners, detergents, dyes or phytosanitaryproducts.

A solid bulk of granulate mass, which is necessary for manufacturingtablets, can be manufactured using two main processes, wet granulationor dry granulation. Tablets may also be manufactured using directcompression. Direct compression relates to the tableting process itselfrather than preparation of the starting material.

In wet granulation, components are typically mixed and granulated usinga wet binder. The wet granulates are then sieved, dried and optionallyground prior to compressing into tablets. Wet granulation is usedextensively in the pharmaceutical industry although it has proven to bea difficult method, mainly because the liquids needed in the granule andtablet manufacturing process often have an adverse effect on thecharacteristics of the active pharmaceutical ingredients (APIs) and/oron the end product such as a tablet.

Dry granulation is usually described as a method of controlled crushingof precompacted powders densified by either slugging or passing thematerial between two counter-rotating rolls. More specifically, powderedcomponents that may contain very fine particles are typically mixedprior to being compacted to yield hard slugs which are then ground andsieved before the addition of other ingredients and final compression toform tablets.

Because substantially no liquids are used in the dry granulationprocess, the issues related to wet granulation are avoided. Although drygranulation would in many cases appear to be the best way to produceproducts such as tablets containing APIs, it has been relatively littleused because of the challenges in producing the desired kind of granulesas well as managing the granulated material in the manufacturingprocess. Known dry granulation methods, as well as the known issuesrelated to them are well described in scientific articles, such as thereview article “Roll compaction/dry granulation: pharmaceuticalapplications” written by Peter Kleinebudde and published in EuropeanJournal of Pharmaceutics and Biopharmaceutics 58 (2004) at pages317-326.

Direct compression is generally considered to be the simplest and themost economical process for producing tablets. However, it may only beapplied to materials that do not need to be granulated before tableting.Direct compression requires only two principal steps; i.e., the mixingof all the ingredients and the compression of this mixture. However,direct compression is applicable to only a relatively small number ofsubstances as the ingredients of the tablets often need to be processedby some granulation technique to make them compressible and/or forimproving their homogeneity and flow-ability.

A component of a tablet is usually described as being either anexcipient or an active ingredient. Active ingredients are normally thosethat trigger a pharmaceutical, chemical or nutritive effect and they arepresent in the tablet only in the amount necessary to provide thedesired effect. Excipients are inert ingredients that are included tofacilitate the preparation of the dosage forms or to adapt the releasecharacteristics of the active ingredients, or for other purposesancillary to those of the active ingredients.

Excipients can be characterized according to their function in theformulation as, for instance, lubricants, glidants, fillers (ordiluents), disintegrants, binders, flavors, sweeteners and dyes.

Lubricants are intended to improve the ejection of the compressed tabletfrom the die of the tablet-making equipment and to prevent sticking inthe punches.

Glidants are added to improve the powder flow. They are typically usedto help the component mixture to fill the die evenly and uniformly priorto compression.

Fillers are inert ingredients sometimes used as bulking agents in orderto decrease the concentration of the active ingredient in the finalformulation. Binders in many cases also function as fillers.

Disintegrants may be added to formulations in order to help the tabletsdisintegrate when they are placed in a liquid environment and so releasethe active ingredient. The disintegration properties usually are basedupon the ability of the disintegrant to swell in the presence of aliquid, such as water or gastric juice. This swelling disrupts thecontinuity of the tablet structure and thus allows the differentcomponents to enter into solution or into suspension

Binders are used to hold together the structure of the tablets. Theyhave the ability to bind together the other ingredients after sufficientcompression forces have been applied and they contribute to theintegrity of the tablets.

Finding the proper excipients for particular APIs and determining theproper manufacturing process for the combination of excipients and APIscan be a time-consuming job that may lengthen the design process of apharmaceutical product, such as a tablet significantly, even by years.

Both the dry and wet granulation methods of the prior art may producesolid bridges between particles within granules that may be undesirablefor example in that they lead to unsatisfactory subsequent tabletcharacteristics. The solid bridges may be caused by partial melting,hardening binders or crystallization of dissolved substances. Partialmelting may for example occur when high compaction force is used in drygranulation methods. When the pressure in the compaction process isreleased, crystallization of particles may take place and bind theparticles together. Introduction of hardening binders is common inpharmaceutical wet granulations when a binder is included in thegranulating solvent. The solvent forms liquid bridges, and the binderwill harden or crystallize on drying to form solid bridges between theparticles. Examples of binders which can function in this way arepolyvinylpyrrolidone, cellulose derivatives (e.g.carboxymethylcellulose) and pregelatinized starch. Substances, e.g.lactose, which can dissolve during a wet granulation process maysubsequently crystallize on drying acting as a hardening binder.

Electrostatic forces may also be important in causing powder cohesionand the initial formation of agglomerates, e.g. during mixing. Ingeneral they do not contribute significantly to the final strength ofthe granule. Van der Waals forces, however, may be about four orders ofmagnitude greater than electrostatic forces and can contributesignificantly to the strength of granules, e.g. those produced by drygranulation. The magnitude of these forces increases as the distancebetween particle surfaces decreases.

In addition to finding a practical manufacturing process for apharmaceutical product, validation of the manufacturing process isessential. Validation means that the process must be able to reliablyproduce a consistently acceptable and predictable outcome each time theprocess is used. Wet granulation methods are quite challenging to managein this respect. The wet granulation process is often quite vulnerableto small changes in manufacturing conditions. For example, variations inthe moisture content of starch in the manufacturing process after dryingmay produce a tablet that is too hygroscopic or which has a reducedshelf life. When a pharmaceutical product is being developed inlaboratory conditions, the conditions can be controlled relativelyeasily. However, the conditions available in mass productionenvironments are typically less accurately controllable thus makingvalidation of the manufacturing process a difficult and time consumingtask. The same can be said about direct compression methods where thequality of the final product depends on the physical properties of theAPI and excipients. A small change in such properties can result, forexample, in segregation and flow-ability problems.

Because of the manufacturing and process validation issues related towet granulation and direct compression methods, it is desirable,particularly in the pharmaceutical industry, to use dry granulationtechniques whenever possible. However, the dry granulation methods knownin the prior art produce granules that are seldom usable in a tabletmanufacturing process. Conflicting process design parameters often leadto compromises where some qualities of the resulting granule product maybe good, but other desirable qualities are lacking or absent. Forexample, the flow characteristics of the granules may be insufficient,the non-homogeneity of the granules may cause segregation in themanufacturing process or capping in tablets, or some of the granules mayexhibit excessive hardness, all of which can make the tableting processvery difficult, slow and sometimes impossible. Furthermore, the bulkgranules may be difficult to compress into tablets. Alternatively oradditionally, the disintegration characteristics of the resultingtablets may be sub-optimal. Such problems commonly relate to thenon-homogeneity and granule structure of the granulate mass produced bythe compactor. For instance, the mass may have too high a percentage offine particles or some granules produced by the compactor may be toodense for effective tableting.

It is also well known in the art that in order to get uniform tabletsthe bulk to be tableted should be homogeneous and should have good flowcharacteristics.

In prior art dry granulation processes such as roll compaction, theresulting bulk is not generally homogeneously flowing, for examplebecause of the presence of relatively large (1-3 mm) and dense granulestogether with very small (e.g. 1-30 μm) particles. This can causesegregation as the large, typically dense and/or hard granules of theprior art flow in a different way to the fine particles when thegranulate mass is conveyed in the manufacturing process, e.g. duringtableting. Because of the segregation, it is often difficult to ensureproduction of acceptable tablets. For this reason, in the art there aresome known devices in which the small particles and sometimes also thebiggest particles are separated from the rest of the granules with thehelp of a fractionating device such as (a set of) vibrating screen(s).This process is generally complicated and noisy and the result is arelatively homogeneously flowing bulk where the granules are hard anddifficult to compress into tablets. Furthermore, the process ofseparating small particles from granules becomes very difficult if thematerial is sticky and the screen-size is not big enough. Generally inthis process the apertures of the screen must have a minimum dimensionof at least 500 μm.

Another problem which occurs in dry granulation methods of the prior artis the difficulty of preparing, in the development stage, a pilot bulkwhich is representative of the production bulk. Thus, the compactionforces and the other compaction parameters used at the laboratory scalecan be very different from those used at the production scale. As aresult the properties, e.g. flow-ability of the production bulk can bevery different from that which has been prepared in a pilot facility.One sieving method applicable in laboratory scale is air sieving. Oneconventional air sieve involves passing a powder through a mesh ofdefined size in order to exclude particles below the specified size (thedesired granules are retained above the mesh and the rejected particlespass below). Air is passed through the mesh to carry away the fineparticles. The problem with the air sieves of the prior art is thattheir capacity is not sufficient for industrial production of granulatemass. Furthermore, the air sieves that rely on mesh size in theseparation of rejected material often exclude desirable small granulesfrom the acceptable granulate mass when separating out the fineparticles from the mass. Yet further, fragile granules may break in thesieving process where undersize particles are sucked through theapertures of the sieve.

Patent application WO 99/11261 discloses dry-granulated granules thatmay comprise API only. In the method disclosed in the application, anair sieve known in the prior art is used for separating fine particles(particles and granules smaller than 150 or 125 μm) from granulescomprising up to 100% of API. The sieving utilizes a sieve whose meshsize is about the maximum size of rejectable particles, e.g. 150 μm. Itseems that the granules of the disclosure have been created usingrelatively high compaction forces since the proportion of fine particles(smaller than 125 μm) after compaction is at most around 26 percent (seetable 1). The method results, following sieving, in a flowinghomogeneous granulate mass that would be expected to comprise generallyhard granules and that substantially is lacking granules and particlessmaller than 150 or 125 μm.

U.S. Pat. No. 4,161,516 teaches a composition for treating airwaydisease using soft tablets or granules for inhalation administration.The method of the patent is suitable for producing granules that aresoft enough to break apart in an airstream.

U.S. Pat. No. 6,752,939 teaches a method and an apparatus for predictingthe suitability of a substance for dry granulation by roller compactionusing small sample sizes.

U.K. Patent 1,558,153 discloses a method for producing organic dyematerial from finely divided particles by compressing said finelydivided particles to produce a coherent mass of material, comminutingsaid coherent mass of material, and recovering granular material in theparticle size range of 100-1000 microns from said comminuted material.The finest particles are removed by air flow.

We have now found an improved method and apparatus for dry granulation.The method may be applicable to a large variety of solid powdersubstances, e.g. APIs and excipients, as well as non-pharmaceuticalproducts e.g. those used in the chemical and food industries.

BRIEF DESCRIPTION OF THE INVENTION

According to the invention, we provide a method for producing granulesfrom a powder, wherein a compaction force is applied to the powder toproduce a compacted mass comprising a mixture of fine particles andgranules and separating fine particles and/or small granules from theother granules by entraining the fine particles and/or small granules ina gas stream.

As explained below, the method may typically be run as a continuousprocess.

Suitably the process is carried out in the substantial absence ofliquid.

The powder, e.g. the APIs and/or excipients usable in pharmaceuticalindustry, to be used in the granulation process of the invention,generally comprises fine particles. Further, the powder may typicallyhave a mean particle size of less than 100, 50 or 20 μm. The fineparticles in the powder may typically have a minimum particle size of 2,5 or 10 μm and maximum size of 150, 100 or 75 μm. The inventors believethat the inventive ideas of the method disclosed herein may beapplicable to form granules also from powder whose minimum particle sizeis smaller than the typical minimum size mentioned above, e.g. 0.001,0.01 or 1 μm.

The mean particle size may be measured for example using a set ofsieves. In case of very fine powders, also microscopy may be used foranalyzing the particle sizes. The flowability of such powders isgenerally insufficient for e.g. tableting purposes. An exemplary methodfor determining sufficient flowability of a mass is disclosed in thedetailed description of FIG. 9.

Hence “fine particles” or “fines” are individual particles typicallyhaving a mean particle size of less than 100, 50 or 20 μm and a maximumsize of 150, 100 or 75 μm.

When several fine particles (e.g. 3, 5, 10 or more) agglomerate to formgranules of maximum size of 150, 100 or 75 μm, they are referred to assmall granules. Granules larger than the maximum size are referred to as“acceptable granules”. Those granules that remain after fine particlesand/or small granules have been entrained by the gas stream, are called“accepted granules”.

The method will typically further comprise the step of collecting theaccepted granules.

The applied compaction force may produce e.g. a compacted ribbon orslug, typically a ribbon. In some embodiments, the thickness of theribbon or slug may be e.g. at least 1.5, 2 or 3 times the mean diameterof accepted granules. In some embodiments, the thickness of the ribbonmay be at least 1, 1.5, 2 or 3 millimeters. The ribbon or slug may thenbe comminuted into granules. The thickness of the ribbon or slug mayhave an effect on the properties of the granules produced by the methodof the present invention.

The ribbon may comprise strongly compacted and weakly compacted powder.In some embodiments, separate compacting means may be used for producingstrongly compacted and weakly compacted powder.

The minimum, optimal and maximum compaction force applicable to thepowder may be dependent on the powder material.

The minimum compaction force may be adjusted to a level high enough toprevent degradation of granule properties, e.g. flowability, duringstorage.

Suitably the compaction force may be provided using a roller compactor.Alternatively it may be provided using a slugging device. Othercompaction methods will be known to a skilled person. The rollercompactor or slugging device may be accompanied by an optional flakecrushing screen or other device, e.g. oscillating or rotating mill,suitable for producing granules from the compacted material. Theoptional step of employing a flake crushing screen or other device,will, if necessary, prepare the material for separation of fineparticles and/or small granules from other granules.

Thus typically the compaction force is applied to the powder by aprocess comprising use of a roller compactor to generate a ribbon ofcompacted powder which is broken up to produce granules e.g. by means ofa flake crusher. The flake crusher or similar device (e.g. a granulatoror a milling device) may permit the upper size of granules to becontrolled e.g. by passing them through a screen. The aperture size ofthe flake crushing screen may be e.g. 0.5 mm, 1.0 mm or 1.2 mm.

The compaction force may be adjusted to be at minimum such that at leastone, five, ten or fifteen percent of the powder substance becomesacceptable granules during compaction and/or fractionating steps, whilethe rest of the material remains fine particles and/or small granules.

Suitably the compaction force is a low compaction force.

If the compaction force used is too low, inventors have observed thatthe granules accepted by the process may be too fragile for e.g.tableting purposes. Such granules may also be too large, e.g. largerthan 3 mm. Fragile granules may not flow well enough or be strong enoughto be handled e.g. in a tableting process. Too fragile granules may alsolose at least some of their flowability over time.

The maximum compaction force may be adjusted so that 75 percent or less,70 percent or less, 65 percent or less, 50 percent or less or 40 percentor less of the powder is compacted into acceptable granules and the restremains as fine particles and/or small granules. The maximum compactionforce is typically up to 500%, 250% or 150% of a minimum compactionforce.

For example the mean particle size of the powder may be less than Y μmand the compaction force may be sufficiently low that 75% or less byweight of the powder is compacted into acceptable granules havingparticle size larger than 1.5×Y μm and at least 150 μm and the restremains as fine particles and/or small granules. For instance the meanparticle size of the powder may be between 1 and 100 μm and thecompaction force is sufficiently low that 75% or less by weight of thepowder is compacted into acceptable granules having particle size largerthan 150 μm (and/or a mean size of 100 μm or greater) and the restremains as fine particles and/or small granules.

The mean particle size may be determined e.g. by dividing the bulk intoa plurality of fractions using a set of sieves and weighing each of thefractions. Such measuring methods are well known to a person skilled inthe art.

When the compaction force is applied by a roller compactor, thecompaction force may be such that the ribbon produced by the rollercompactor has a tensile strength of around 40-250N i.e. at least 40N,50N or 60N and less than 250N, 200N or 150N when the thickness of theribbon is about 4 mm. The area of the measured ribbon may be e.g. 3 cm×3cm. The tensile strength of the ribbon may be measured e.g. using deviceof make MECMESIN™ (Mecmesin Limited, West Sussex, UK) and model BFG200N.

The compaction force may also be such that the bulk volume of the powderis reduced by around 7-40% i.e. at least 7%, 10% or 13% and less than40%, 35% or 30% following compaction.

The maximum and minimum compaction forces will of course depend on theparticular compactor and powder used. Thus, for example the minimumcompaction force may be adjusted so that it is the minimum possiblecompaction force, 15 kN, 20 kN or 30 kN in a Hosokawa™ (Osaka, Japan)Bepex Pharmapaktor L200/50P roller compactor. The maximum compactionforce may also be adjusted so that it is 80 kN or less, 70 kN or less,60 kN or less or 45 kN or less in a Hosokawa™ Bepex PharmapaktorL200/50P roller compactor.

Typically a suitable compaction force is 60 kN or less e.g. 45 kN orless. Typically, a suitable compaction force is 12 kN or more e.g. 16 kNor more in a Hosokawa™ Bepex Pharmapaktor L200/50P compactor orequivalent.

The maximum compaction force may also be adjusted so that substantiallyno solid bridges are formed in the granules of the resulting mass e.g.due to heating of the mass. Some compactors known in the art providemeans for cooling the compacted material to alleviate the heating issuesintroduced by use of high compaction forces. With the method and systemof the present invention, this precaution is unnecessary.

The compaction force may be adjusted using a method appropriate for thecompactor employed, for example by control of the rate of feed into thecompactor.

The above mentioned preferred compaction forces are low and, asexplained elsewhere herein, granulate mass compacted using such lowforces and processed according to the invention appears to retain goodproperties of compressibility into tablets. This remark appears to beespecially true when the granulate mass comprises a binder.

The gas stream may be provided by any suitable means, e.g. a generatorof negative pressure i.e. a vacuum pump such as a suction fan. The gasstream, e.g. air, may be directed through a fractionating chamber. Thegas stream separates at least some fine particles and/or small granulesfrom the mass comprising acceptable granules, small granules and fineparticles. The separated fine particles and/or small granules entrainedin the gas stream may be transferred from the fractionating chamber to aseparating device, e.g. a cyclone where the carrier gas is separatedfrom the fine particles and/or small granules. The fine particles and/orsmall granules may then be returned to the system for immediatere-processing (i.e. they are re-circulated for compaction) or they maybe placed into a container for later re-processing.

For suitable protection of the system and environment, suitably the gasinlet of the vacuum pump is provided with a receiver filter to trap anyparticles that may pass through the pump. Most suitably the gas inlet ofthe vacuum pump is provided with a second filter (safety filter) inseries with the receiver filter.

Thus, conveniently, fine particles and/or small granules are separatedfrom the acceptable granules by means of an apparatus comprisingfractionating means. Desirably, the fractionating means comprises afractionating chamber.

As discussed in greater detail in the examples, the largest acceptablegranules exiting from the fractionating chamber are usually larger insize than the largest granules entering the fractionating chamber. Theinventors believe that a process whereby small granules and/or fineparticles agglomerate with larger granules takes place during theconveyance of the material through the fractionating chamber.

Suitably the direction of the flow of the gas stream has a componentwhich is contrary to that of the direction of flow of the compacted massin general and accepted granules especially. Typically the direction ofthe flow of the gas stream is substantially contrary to (e.g. around150-180° to), and preferably contrary to that of the direction of flowof the compacted mass.

The gas may, for example, be air (suitably dry air). In someembodiments, the gas may contain a reduced proportion of oxygen. In someembodiments, the gas may be e.g. nitrogen.

The carrier gas may suitably be re-circulated in the process. This isespecially beneficial for economic reasons when the carrier gas is notair.

The fractionating means may be static, i.e. it comprises no movingparts. Alternatively the fractionating means may be dynamic, i.e. thefractionating means comprises some moving parts.

In an method according to the invention fine particles and/or smallgranules may be separated and removed from the granules by means of anapparatus comprising two or more (e.g. two) fractionating means inseries. In some embodiments, the arrangement may comprise a plurality ofstatic and/or dynamic fractionating means that may be arranged inparallel or in series. In one embodiment, a dynamic fractionating meansmay be connected in series to a static fractionating means.

The fractionating means may comprise means to guide a gas stream intothe fractionating means, means to put the compacted mass into motion andmeans to guide removed fine particles and/or small granules entrained inthe gas stream from the fractionating means, e.g. for re-processing. Thecompacted mass may be put into motion simply by the effect ofgravitation and/or by mechanical means.

Advantageously the fractionating means does not require passage of thecompacted mass through any sieve (such as a mesh screen). Sieves have atendency to break up lightly compacted granules, therefore avoidance ofuse of a sieve permits lightly compacted granules, with their favorableproperties, to be preserved e.g. for tableting. Moreover sieves areeasily clogged, which disrupts the process, especially when run incontinuous operation. Additionally, the eye size of a sieve may varyduring the period of operation due to transient clogging.

A number of fractionating means are known which may be suitable for usein performance of the invention. The fractionating means may for examplecomprise a device for example a moving device e.g. a rotating device,such as a cylinder (or cone), along the axis of which the compacted massis moved in the gas stream. Movement of the compacted mass may be bygravitational means or it may be facilitated by mechanical means, or byfeatures of the device (e.g. cylinder). The rotating device may compriseat least one structure for guiding the compacted mass inside therotating device, such as by provision of a spiral structure. The spiralstructure may be formed of channels or baffles which guide the movementof the compacted mass. A component of gravitational assistance orresistance may be provided by tilting the axis of the rotating device.Suitably the compacted mass moves along a helical path within thedevice. This is advantageous since it increases the path length of thecompacted mass and thereby the residence time in the device, and this isexpected to increase the efficiency of fractionation. Suitably thelength of the helical path is at least twice the linear length of travelalong the axis of the device, e.g. at least 2, 3 or 5 times. Suitablythere is also at least some movement of the compacted mass relative tothe device itself which may thereby create some friction between themass and the wall of the device. The friction may contribute to thetriboelectrification phenomenon that may occur in the fractionatingdevice.

The fractionating means may contain one or more apertures through whichfine particles and/or small granules are entrained. In one specificembodiment of the invention the gas stream enters the rotating devicealong its axis (in the opposite sense to movement of the compacted mass)and exits the rotating device through one or more apertures(perforations) in the side walls of the rotating device. One aperture isthe minimum, however two or more (e.g. 4, 8, 12 or more) may besuitable.

As noted above, the fractionating means may comprise a device forexample a moving device, e.g. a rotating device to move the compactedmass in the fractionating means. The device may comprise one or moreapertures through which the gas stream flows into and out of the deviceand through which the fine particles and/or small granules areentrained. The apertures through which gas flows out of the device maybe substantially larger than rejectable fine particles, e.g. at least50%, 100% or 150% of the average diameter of accepted granules. Inabsolute terms, the apertures may for example have a minimum dimensionof around 250 μm, 500 μm or 750 μm or more. This helps prevent theapertures from clogging even when relatively high volumes of fineparticles of possibly sticky material need to be separated from thecompacted mass. In this sense, the device significantly differs from anair sieve of the prior art where the sieve mesh size must be of aboutthe same size as the largest rejected particle. Instead of relying onthe mesh size in the sieving, the fractionating device of the inventionrelies on the gas stream's ability to entrain fine particles from themoving compacted mass. The determination of the size of acceptablegranules may be achieved e.g. by balancing their gravitational force(together with other forces, e.g. mechanical and centrifugal forces)against the force of the gas stream.

In another embodiment, the fractionating means may comprise acylindrical device having a first orifice at the top of the device forentry of material from the compactor, a second orifice at the bottom ofthe device for exit of accepted granules as well as entry of carrier gasand a third orifice for exit of carrier gas located at or near the topof the device and above the first orifice. In use the compacted powderenters the device through the first orifice and passes through thedevice under the influence of gravitation and the carrier gas enters andexits the device through the second and third orifices respectively. Theaccepted granules leave the device through the second orifice. Therejected fine particles and/or small granules are carried by the carriergas through the third orifice. The third orifice is orientated above thefirst orifice so that no component of the compacted mass may leave thedevice through the third orifice without having been entrained contraryto the influence of gravitation (i.e. the compacted mass does not justpass from the first orifice to the third orifice without residing in thedevice for any significant length of time). Suitably the first orificeis provided with valves (e.g. flaps) so that carrier gas does not exitthrough it.

In another embodiment, the fractionating means may comprise a devicehaving a frustoconical lower section and optionally a cylindrical uppersection and having a first orifice at the top of the device for entry ofmaterial from the compactor, a second orifice at the apex of thefrustoconical section for exit of accepted granules as well as entry ofcarrier gas and a third orifice for exit of carrier gas orientatedtangentially to the perimeter of the device and above the first orifice.In use the compacted powder enters the device through the first orificeand passes through the device under the influence of gravitation and thecarrier gas enters and exits the device through the second and thirdorifices respectively causing a vortex effect to be created within thedevice. Such a device may be referred to as a vortex device. Theaccepted granules leave the device through the second orifice. Therejected fine particles and/or small granules are carried by the carriergas through the third orifice. The third orifice is orientated above thefirst orifice so that no component of the compacted mass may leave thedevice through the third orifice without having been entrained contraryto the influence of gravitation (i.e. the compacted mass does not justpass from the first orifice to the third orifice without residing in thedevice for any significant length of time). In this embodiment, thecompacted mass (or at least components of it) follows a helical paththrough the device due to creation of the vortex. Suitably the length ofthe helical path is at least twice the linear length of travel along theaxis of the device, e.g. at least 2, 3 or 5 times. There may also befriction between the mass moving in the vortex and the stationary wallof the device. The friction may contribute to the triboelectrificationphenomenon possibly occurring in the fractionating device. Suitably thefirst orifice is provided with valves (e.g. flaps) so that carrier gasdoes not exit through it.

In some embodiments, the compacted mass may flow during thefractionation e.g. against a wall of a rotating cylinder, a conveyorbelt or a vortex device and in particular against a conveyor belt. Forexample, at least some granules of the compacted mass may be put into amotion e.g. by making the compacted mass flow in the fractionatingdevice against gravitation e.g. at a suitable angle such as against aninclined conveyor belt which moves against gravitation. Because of theflow, the movement of an individual acceptable granule of the mass mayhave a spinning component.

Hence, according to this embodiment, there is provided a fractionatingdevice adapted to separate and remove fine particles and/or smallgranules from a compacted mass by entraining the fine particles and/orsmall granules in a gas stream which comprises an enclosed chamber,typically of square or rectangular cross-section, containing an inclinedconveyor belt which moves against gravitation such that compacted massentering the fractionating device is separated into an accepted fractionwhich flows with the force of gravitation against the movement of theconveyor belt and a rejected fraction of fine particles and/or smallgranules which is entrained in the gas stream and flows against theforce of gravitation with the movement of the conveyor belt.

Suitably the fractionating means is provided with means to preventclogging or build-up. For example it may be provided with a vibrating orultrasound emitting means. Alternatively when the fractionating meanscontains apertures (e.g. in the case of a rotating cylinder with one ormore apertures) said apertures may be unclogged by blowing pressurizedgas e.g. air through or across the apertures.

Some of the fine particles and/or small granules may be agglomerated toother granules in the fractionating means by means of the individual orcombined influence of the carrier gas stream, mechanical forces,attractive forces and electrostatic forces, for example. Thus, theprocess may produce granules that are larger than what is produced bythe flake crushing screen of the system. In some embodiments, the degreeof agglomeration of the compacted mass in the fractionating phase may besignificant.

The movement of the mass in the gas stream may be achieved by applying,for example, a mechanical force, gravitational force, centrifugal forceor a combination of these. In some embodiments, a mechanically movingcomponent in the fractionating means may not be needed at all to realizethe benefits of the present invention. In some embodiments, theacceptable granules fall in a gas stream e.g. by effect of gravitationforce and unacceptable particles and granules are moved to at leastpartially opposite direction by the gas stream. Suitably, however, thecompacted mass is moved in the gas stream by means including mechanicalmeans.

Typically the average residence time of the compacted mass within thefractionating means is at least 1 second or 2 seconds, perhaps even atleast 5 seconds, although the desired fractionating effect (includingany agglomerating effect) may be achievable also in a time frame shorterthan that. Residence time may be extended e.g. by providing a helicalpath.

It should also be noted that the rejected fraction of the mass may alsocontain e.g. at least 10%, 20% or 25% of acceptable granules that havethus also been entrained in the gas stream in the fractionating step ofthe process. By allowing some recycling of acceptable granules theoverall apparatus may be made more efficient and easier to maintain asclogging of fractionating device may be more easily avoided. Theserejected acceptable granules may be conveyed to the beginning of thegranulating process along with the other rejected material forreprocessing. For efficiency, we prefer that at maximum 30, 45, 60 or 75percent of acceptable granules are re-cycled with the fines. Theinventors have not observed any detrimental effect on the granulate masscaused by recycling. This is attributable to the use of low compactionforce.

According to a further feature of the invention we provide an apparatuscomprising compacting means and means adapted to separate fine particlesand/or small granules from a compacted mass by entraining the fineparticles and/or small granules in a gas stream, e.g. air.

Thus an apparatus according to the invention may be characterized inthat said fractionating means for example comprising a rotating device(see e.g. (401) in the drawings) comprises at least one exit aperture(see e.g. (511) in the drawings) through which said gas stream flows outof said means said aperture being large enough to allow a granule havingacceptable properties (e.g. flowability, tabletability, size, especiallysize) to flow out of said device.

The apparatus may further comprise a separating means (e.g. a cyclone)to separate the gas stream from the particles removed from the compactedmass.

A further specific aspect of the invention provides an apparatus for drygranulation, characterized in that the apparatus comprises compactingmeans capable of producing compaction force which when applied to apowder produces a compacted mass comprising a mixture of fine particlesand granules and fractionating means adapted to separate and remove fineparticles and/or small granules from the granules by entraining the fineparticles and/or small granules in a gas stream. The apparatus maysuitably comprise a roller compactor to generate a ribbon of compactedpowder which is then broken up to produce granules. Said apparatus maybe characterized in that said fractionating means comprises means tomove said compacted mass. Said means to move said compacted mass maycomprise means to move said compacted mass by gravitational ormechanical means. An apparatus according to the invention may, forexample, be characterized in that said fractionating means comprises atleast one structure (see e.g. (403) in the drawings) for guiding saidcompacted mass inside said fractionating means.

An apparatus according to the invention may comprise means to providethe gas stream wherein the direction of the flow of the gas stream has acomponent which is contrary to that of the direction of flow of thecompacted mass (e.g. the direction of the flow of the gas stream issubstantially contrary to that of the direction of flow of the compactedmass).

An apparatus according to the invention is typically provided with afractionating means which comprises a device such as a rotating device(e.g. a cylinder or cone, especially a cylinder) along the axis of whichthe compacted mass is moved in said gas stream. Movement of thecompacted mass along the axis of the rotating device may be facilitatedby means of a spiral structure which guides the movement of thecompacted mass. The fractionating means e.g. the rotating device maycontain one or more apertures through which the fine particles and/orsmall granules are entrained. When it is desired to produce granules ofmean size x, the apertures may have a minimum dimension of 0.5x, or 1.0xor even 1.5x. In absolute terms the apertures may, for example, have aminimum dimension of 250 μm, 500 μm or 750 μm.

The apparatus according to the invention may also comprise processmonitoring and/or controlling means. For example, the amount of material(typically the weight of material) being in circulation in variouscomponents of the apparatus may be monitored and/or controlled by suchmeans.

In order to keep the device in balance for continuous operation,suitably the amount (weight) of powder being conveyed to the compactionmeans will be measured and controlled as will the amount (weight) ofaccepted granules being collected and optionally also the amount(weight) of compacted mass leaving the compactor prior to entering thefractionating device. Means of measurement and control include provisionof scales to measure weight at various points in the system (e.g. at thereservoir of powder, the collector of accepted granules and optionallyafter the compactor and prior to the fractionating device).

In general terms it is desirable: (a) to control the amount of materialin the apparatus, (b) to measure flowability of accepted granules, (c)to measure output rate of accepted granules and/or (d) to monitorprogress of material in the fractionating means (e.g. by means ofprovision of a window therein).

Suitably control means are provided to keep the gas flow as steady aspossible, especially when one and the same gas stream is used forfractionating as for pneumatic transport.

The invention also provides a fractionating device adapted to separatefine particles and/or small granules from a compacted mass by entrainingthe fine particles and/or small granules in a gas stream which comprisesa device (e.g. a moving device such as a rotating device) and forexample a cylinder or cone, along the axis of which the compacted massis moved in said gas stream and which rotating device contains one ormore apertures through which fine particles and/or small granules areentrained.

Suitably the compacted mass moves along a helical path within thedevice. Suitably the length of the helical path is at least twice thelinear length of travel along the axis of the device, e.g. at least 2, 3or 5 times. Suitably there is also at least some movement of thecompacted mass relative to the device itself which may thereby createsome friction between the mass and the wall of the device.

In one embodiment, the fractionating device comprises a fractionatingchamber there being, mounted inside the chamber, an open ended cylinder(or cone). The open ended cylinder (or cone) may be rotatably supportedon rollers. Carrier gas is supplied to the inside of the open endedcylinder (or cone). The jacket of the cylinder (or cone) may beperforated with one or more apertures through which fine particlesand/or small granules are entrained in the carrier gas. As describedelsewhere, the entrained fine particles and/or small granules may becaptured for recycling.

In some embodiments, the gas flow in the fractionating chamber may bearranged to be an at least partially turbulent flow. In some otherembodiments, the gas flow in the fractionating chamber may be arrangedto form a laminar flow, e.g. a vortex. In some embodiments, some of thegas flow may be turbulent and some may be laminar.

In the method and apparatus according to the invention, pneumatictransport may be used. Suitably, the gas used to entrain the fineparticles in the compacted mass is in fluid communication with thecarrier gas used to convey materials in continuous operation. In someembodiments, different gas streams may be used for fractionation andconveying. Suitably the gas stream employed in the pneumatic conveyor isthe same gas stream as is used to entrain the fine particles and/orsmall granules. In yet further embodiments, conveying of the materialmay be implemented using some mechanical conveying means, e.g. screw orbelt conveyor while fractionation means utilize some suitable gasstream. Construction of such embodiments following teachings of thisdisclosure is obvious to a person skilled in the art.

Thus, suitably the powder for compaction is conveyed from a reservoir tothe means to apply compaction force by means comprising use of apneumatic conveyor.

The pneumatic transport may use a device, e.g. a cyclone, for separatingcarrier gas from fine particles. The device may be for example capableof continuous operation at an about even gas flow rate, in the sensethat the carrier gas stream used in the fractionating process is notdisturbed by pressure changes, e.g. by pressure shocks, such as arerequired to keep filters of various types open.

“Continuous operation” in this context means ability to operate withoutmaintenance or other interruptions for at least one hour, eight hours or24 hours.

The carrier gas stream(s) used in the fractionating process and/or thepneumatic conveyance (which suitably are one and the same gas stream)are suitably created by a generator of negative pressure (e.g. a vacuumpump) which draws gas in from another part of the system, typically atthe outlet to the fractionating means. A suction fan is a typicalexample of a vacuum pump. The vacuum pump is suitably provided with atleast one filter to capture any particles that without filtering wouldbe drawn through the pump. Most suitably two filters are provided inseries (i.e. a receiver filter and a safety filter).

One aspect of the invention is a dry-granulate mass containing granulesobtainable according to the method of the invention.

Without being limited by theory, the inventors believe that the productof the process of the invention is influenced by triboelectric effectscaused by passage of powder through the system. It is suggested in priorart that small particles may have a tendency to develop a negativecharge whereas larger particles develop a positive charge (or at least aless negative charge) (see e.g. article “Generation of bipolar electricfields during industrial handling of powders” by Ion. I. Inculet et al,Chemical Engineering Science 61 (2006), pages 2249-2253) e.g. whenconveyed by a gas stream or otherwise moved in a gas stream. Hence atleast some and possibly most of the granules of the dry granule massappear to comprise a compressed core containing fine particles ofmaterial associated by Van der Waals forces and a coating layercontaining fine particles and/or small granules of said materialassociated with said compressed core by electrostatic forces. Theinventors have also discovered that, at least in some cases, e.g. withpowder containing binder excipient, if granules obtained by the processof the invention are taken and a proportion of the starting materialcomposed of fine particles is added back (e.g. up to 15% fine particlesis added back to a granulate mass that may already have e.g. 20% of fineparticles and/or small granules, e.g. mass of “flowability example 3”)then the homogeneity, flowability and tabletability of the granulatemass is not adversely affected in a significant manner. The added finesare, perhaps, taken into the porous surface of granules formed by theprocess of the invention. Inventors thus believe that in someembodiments, it may be possible to use granules of some embodiments ofthe invention as “carrier granules” that may absorb e.g. into the poresof the granules up to 10%, 20%, 30% or more of fine particles and/orsmall granules comprising same or different material as the carriergranules. The flowability of such mixture may be at an excellent, verygood or good level.

Granulate mass produced according to the invention is believed to havegood compressibility because at least the surface of the granules isporous. The compressibility of the granulate mass of the invention maybe good, i.e. it may have a Hausner ratio of greater than 1.15, 1.20 or1.25. The compaction force of the present invention may be adjusted sothat the compressibility as indicated by the Hausner ratio stays at goodlevel.

The Hausner ratio may be calculated using formula p_(tap)/p_(bulk) wherep_(tap) represents tapped bulk density of the granulate mass andp_(bulk) represents the loose bulk density of the granulate mass. Thebulk densities may be measured by pouring 50 mg of granulate mass into aglass cylinder (e.g. make FORTUNA, model 250:2 ml) having an innerdiameter of 3.8 mm. After pouring the mass into the cylinder, the volumeof the mass is observed from the scale of the glass cylinder and loosebulk density of the mass is calculated. To measure the tapped bulkdensity, the glass cylinder is tapped 100 times against a table topusing a force comparable to a drop from the height of 5 cm. The volumeof the tapped mass is observed from the scale of the glass cylinder andtapped bulk density of the mass is calculated.

Surprisingly, and contrary to what is taught in the prior art, e.g. inWO99/11261, the compressibility of the granulate mass of the inventiondoes not generally exhibit any negative influence on the flowability ofthe granulate mass. For example, a granulate mass of an embodiment ofthe invention with Hausner ratio above 1.25 generally exhibits very goodor excellent flow characteristics.

Porous, well-flowing granules are generally desired in thepharmaceutical industry for example because it is possible to produceenhanced tablets from porous granules. Such tablets may for exampledisintegrate substantially quicker than tablets manufactured from densegranules. Further, tablets compressed from porous granules often showhigher tensile strength than tablets compressed from dense granules.High tensile strength is often desirable for tablets as such tablets areeasier to package and transport than fragile tablets.

The granulate mass may be tabletable so that using standard tabletingtechniques, e.g. using tableting forces available in widely usedtableting machines, it is possible to form it into tablets havingtensile strength of at least 5N, 10N or 15N. Tensile strength may bemeasured for example using a measuring device of make MECMESIN™(Mecmesin Limited, West Sussex, UK) and model BFG200N.

The granulate mass may comprise at least one API and/or at least oneexcipient usable in pharmaceutical products. In one embodiment thegranulate mass comprises (e.g. consists of) at least one (e.g. one) API.In another embodiment the granulate mass comprises at least one (e.g.one) API and at least one (e.g. one) excipient. The granulate mass maycontain a total amount of active pharmaceutical ingredient of at least60% e.g. at least 80% w/w. The granulate mass may contain one or moreexcipients e.g. a binder and/or a disintegrant in an amount of 40% orless e.g. 20% or less, for example 5-40% e.g. 5-20% w/w.

The invention also provides a process for preparing a tablet whichcomprises compressing a dry-granulated granulate mass manufacturedaccording to the method of the invention optionally blended with one ormore additional excipients. Said one or more additional excipientstypically comprises a lubricant e.g. magnesium stearate. A relativelylow amount of lubricant e.g. 0.1-5% e.g. 0.1-0.5% w/w may be employed. Atablet obtainable by such a process is another aspect of the invention.

The granules of the invention may be especially useful in preparingmultilayer tablets. In multilayer tablets it seems that it isadvantageous to use porous granules, as may be prepared according to theprocess of the invention, to prepare the layers, especially the innerlayers. This may facilitate adherence of the layers to each other andparticularly adherence of the outer layers to the inner layers. Use oflarger size granules, e.g. of size greater than 200 micron or evengreater than 400 or 500 micron can also facilitate adherence of layersto each other since it results in a less smooth surface aftercompression. Multilayer tablets may typically be prepared by firstcompressing the layers individually and then compressing the layerstogether. Granules of the invention could be used in all the layers orjust some of the layers (e.g. the outer layers).

The granulation method and apparatus of the invention can be applied formany purposes in the pharmaceutical, chemical and food industries. Themethod and apparatus use compaction force, suitably low compactionforce, and gas stream to form granules of desired properties. Thecompaction force may be adjusted so that introduction of solid bridgesis substantially avoided in the compaction step. The method andapparatus are adapted to treat the product granules gently to avoidbreaking them, to separate fine particles and/or small granules from theacceptable granules, and optionally to re-circulate the rejectedmaterial for re-processing in the system. The apparatus and method canbe made easily adjustable, controllable and more or less continuouslyoperable.

The size distribution and/or flowability of the granules produced by theapparatus may be analyzed in real-time and the size distribution of thegranules may be adjusted based on the analysis. For example, the flakecrushing screen (see FIGS. 1 a and 1 b below) may be such that theaperture size of the mesh used for flake crushing can be varied by usingsome adjustment means. Another adjustable parameter typically is the gasflow rate of the fractionating device.

The method can be made economic as it allows re-processing of rejectedmaterial with practically no waste, and can be adapted to provide fasttreatment of large amounts of material. The apparatus of the presentinvention may be adapted to be easy to clean and assemble and theprocess may be adapted to be stable and predictable thus making it easyto control.

Because of, for example, the homogeneity and/or flowability of theresulting granules, issues related to segregation can be avoided. Themethod of the present invention can be used in both small and largescale applications. Thus, when a product, e.g. granules or a tabletcontaining API(s) has been successfully developed under laboratoryconditions, the time required to set up a validated large-scalemanufacturing process can be short.

Because the method and apparatus of the present system is capable ofgranulating a variety of powders, including those consisting of 100%APIs, it is possible to produce granulate mass from separate substancesin separate granulation processes and mix the resulting granulestogether after their individual granulations. Granulating API andexcipients separately before blending may be advantageous e.g. when rawmaterials have very different particle sizes.

Different kinds of end products, including tablets, oral suspensions andcapsules may be manufactured from the granulate mass.

According to the invention, we also provide a process for manufacture ofa tablet which comprises tableting granules according to the invention,or granules made using the method of the invention.

We have found that the method of the present invention may be used forproducing granules of large variety of powder substances usable inpharmaceutical industry.

The method of the present invention may thus be applicable to producinggranules and tablets of the invention from material comprising APIs ofone or multiple classes of APIs, the classes including for exampleantipyretics, analgesics, antiphlogistics, hypnosedatives,antihypnotics, antacids, digestion aids, cardiotonics, antiarrhythmics,antihypertensives, vasodilators, diuretics, antiulcers, antiflatulents,therapeutic agents for osteoporosis, antitussives, expectorants,antiasthmatics, antifungals, micturition improvers, revitalizers,vitamins and other orally administered agents. APIs can be used singlyor two or more of them can be used in combination.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising specificAPIs, for example paracetamol, acebutolol, metformin, fluoxetine,aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapirin,salicylamide, lactyl phenetidine, isothipendyl, diphenylpyraline,diphenhydramine, difeterol, triprolidine, tripelennamine, thonzylamine,fenethazine, methdilazine, diphenhydramine salicylate, carbinoxaminediphenyldisulfonate, alimemazine e.g. as tartrate, diphenhydramine e.g.as tannate, diphenylpyraline e.g. as teoclate, mebhydrolin napadisylate,promethazine e.g. as methylene disalicylate, carbinoxamine e.g. asmaleate, chlorophenylamine e.g. as di-maleate, chlorophenylamine e.g. asd-maleate, difeterol e.g. as phosphate, alloclamide, cloperastine,pentoxyverine (carbetapentane), tipepidine, dextromethorphan e.g. ashydrobromide, dextromethorphan e.g. as phenolphthalinate, tipepidinee.g. as hibenzate, cloperastine e.g. as fendizoate, codeine e.g. asphosphate, dihydrocodeine e.g. as phosphate, noscapine,dl-methylephedrine e.g. as saccharin salt, potassium guaiacolsulfonate,guaifenesin, caffeine, anhydrous caffeine, vitamin B1 and derivativesthereof, vitamin B2 and derivatives thereof, vitamin C and derivativesthereof, hesperidin and derivatives thereof and salts thereof, vitaminB6 and derivatives thereof and, nicotinamide, calcium pantothenate,aminoacetate, magnesium silicate, synthetic aluminum silicate, synthetichydrotalcite, magnesium oxide, aluminum glycinate, coprecipitationproduct of aluminum hydroxide/hydrogen carbonate, coprecipitationproduct of aluminum hydroxide/calcium carbonate/magnesium carbonate,coprecipitation product of magnesium hydroxide/potassium aluminumsulfate, magnesium carbonate, magnesium aluminometasilicate, ranitidine,cimetidine, famotidine, naproxen, diclofenac, piroxicam, azulene,indometacin, ketoprofen, ibuprofen, difenidol, promethazine, meclizine,dimenhydrinate, fenethazine e.g. as tannate, diphenhydramine e.g. asfumarate, scopolamine e.g. as hydrobromide, oxyphencyclimine,dicyclomine, metixene, atropine methylbromide, anisotropine e.g. asmethylbromide, scopolamine methylbromide, methylbenactyzium e.g. asbromide, belladonna extract, isopropamide e.g. as iodide, papaverine,aminobenzoic acid, cesium oxalate, aminophylline, diprophylline,theophylline, isosorbide e.g. as dinitrate, ephedrine, cefalexin,ampicillin, sucralfate, allylisopropylacetylurea, bromovalerylurea, andwhere appropriate (other) pharmaceutically acceptable acid or baseaddition salts thereof (e.g. those salts which are in common usage) andother such pharmaceutically active ingredients described in EuropeanPharmacopoeia, 3^(rd) Edition and one, two or more of them incombination.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising furtherspecific APIs, for example ibuprofen e.g. as sodium or sodiummonohydrate, alclometasone dipropionate, allopurinol, alprazolam,amcinonide, amitriptyline e.g. as HCl, amoxicillin, atenolol, atracuriume.g. as besylate, azithromycin, aztreonam, beclomethasone,beclomethasone dipropionate, betamethasone, betamethasone acetate,betamethasone buteprate, betamethasone dipropionate, betamethasonedisodium phosphate, betamethasone valerate, bivalirudin, bleomycin e.g.as sulfate, bortezomib, bromocriptine e.g. as mesilate, budesonide,buprenorphine e.g. as hydrochloride, butorphanol e.g. as tartrate,cabergoline, calcipotriene, calcitonin salmon, carbamazepine, carbidopa,carboplatin, carvedilol e.g. as phosphate, cefadroxil, cefdinir,cefprozil, cephalexin, chlormadinone e.g. as acetate, cilostazol,cisplatin, clarithromycin, clobetasol e.g. as propionate, clobetasonebutyrate, clomiphene e.g. as citrate, clomipramine e.g. as HCl,clonazepam, clopidogrel e.g. as HBr, cyproterone e.g. as acetate,darifenacin, daunorubicin e.g. as HCl, deferasirox, deferoxamine e.g. asmesilate, deflazacort, deprodone propionate, desmopressin e.g. asacetate, desonide, desoximetasone, diazoxide, dicloxacillin, diflorasonee.g. as diacetate, difluprednate, dihydro-a-ergocriptine e.g. asmesylate, dihydroergocristine e.g. as mesylate, dihydroergotamine e.g.as mesylate, dihydroergotoxine e.g. as mesylate, diltiazem e.g. as HCl,docetaxel, dorzolamide e.g. as HCl, doxepin e.g. as HCl, doxorubicine.g. as HCl, epirubicin e.g. as HCl, eptifibatide, ergometrine e.g. asmaleate, ergotamine e.g. as tartrate, etodolac, etoposide, famciclovir,fludarabine e.g. as phosphate, fludrocortisone acetate, flumethasone,flumethasone e.g. as pivalate, flunisolide e.g. as anhydrous,fluocinolone e.g. as acetonide, fluocinonide, fluorometholone,fluticasone e.g. as propionate, fluvoxamine e.g. as maleate, formoterole.g. as fumarate, fulvestrant, furosemide, gabapentin, galantamine e.g.as HBr, gemcitabine e.g. as HCl, gemfibrozil, halcinonide, haloperidol,haloperidol e.g. as decanoate, hydrochlorothiazide, idarubicin e.g. asHCl, imatinib, imipramine e.g. as HCl, imiquimod, indomethacin,labetalol e.g. as HCl, latanoprost, leflunomide, leuprolide/leuproreline.g. as acetate, levodopa, lisinopril, lisuride e.g. as maleate,loperamide, lovastatin, medroxyprogesterone acetate, megestrol e.g. asacetate, memantine, metaxalone, metergoline, methyldopa,methylergometrine meleate, methylprednisolone, metoprolol succinate,metoprolol e.g. as tartrate, mirtazapine, mitomycin, mitoxantrone e.g.as HCl, mometasone furoate, mupirocin, mupirocin e.g. as calcium,nabumetone, naproxen e.g. as sodium, nefazodone e.g. as HCl,nicergoline, norelgestromin, octreotide e.g. as acetate, olanzapine,olmesartan e.g. as medoxomil, ondansetron e.g. as HCl, oxaliplatin,oxazepam, paclitaxel, pancuronium e.g. as bromide, pantoprazole e.g. assodium sesquihydrate, paramethasone acetate, paroxetine e.g. as HCl,pemetrexed diacid, pentoxifylline, pergolide e.g. as mesilate,pioglitazone e.g. as HCl, probenecid, prostaglandin, rocuronium e.g. asbromide, rosuvastatin e.g. as calcium, salbutamol (albuterol) e.g. assulfate, sertraline e.g. as HCl, sildenafil, silymarine, solifenacin,tamoxifen e.g. as citrate, telmisartan, terazosin e.g. as HCl,terguride, teriparatide, ticlopidine e.g. as HCl, timolol e.g. asmaleate, tobramycin, tobramycin e.g. as sulfate, torsemide, trazodone,triamcinolone, triamcinolone acetonide, trimethoprim, trimipramine e.g.as maleate, valaciclovir e.g. as HCl, vecuronium e.g. as bromide,venlafaxine e.g. as HCl, verapamil, zaleplon, zoledronic acid, zolpidemand zonisamide or a (or an alternative) pharmaceutically acceptable saltthereof, e.g. the HCl salt.

In one embodiment the API is not ibuprofen sodium or a hydrate thereof.In one embodiment the API is not ibuprofen sodium monohydrate. Inanother embodiment the API is not ibuprofen sodium dihydrate.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising furtherspecific APIs, for example lamotrigine, ondansetron e.g. ashydrochloride, lamivudine, valacyclovir e.g. as hydrochloride,paroxetine e.g. as hydrochloride, zidovudine, carvedilol, rosiglitazonee.g. as maleate, abacavir e.g. as sulfate, bupropion e.g. ashydrochloride, topiramate, rabeprazole e.g. as sodium, galantamine e.g.as hydrobromide, risperidone, oxybutynin e.g. as chloride, repaglinide,venlafaxine e.g. as hydrochloride, ramipril, pravastatin e.g. as sodium,aripiprazole, efavirenz, levofloxacin, escitalopram e.g. as oxalate,memantine e.g. as hydrochloride, tenofovir, disoproxil e.g. as fumarate,simvastatin, alendronate e.g. as sodium, losartan e.g. as potassium,montelukast e.g. as sodium, finasteride, ezetimibe, rizatriptan e.g. asbenzoate, mycophenolate mofetil, capecitabine, granisetron e.g. ashydrochloride, ritonavir, fenofibrate, bosentan, modafinil, clopidogrele.g. as bisulfate, irbesartan, irbesartan-hydrochlorothiazide,drospirenone, desloratadine, lansoprazole, levetiracetam, quetiapinee.g. as fumarate, anastrozole, bicalutamide, candesartan cilexetil,zolmitriptan and sumatriptan e.g. as succinate or a (or an alternative)pharmaceutically acceptable salt thereof, e.g. the HCl salt.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising furtherspecific APIs, for example atorvastatin e.g. as calcium, amlodipine e.g.as besylate, raloxifene e.g. as hydrochloride, tadalafil, pioglitazonee.g. as hydrochloride, duloxetine e.g. as hydrochloride, atomoxetinee.g. as hydrochloride, terbinafine e.g. as hydrochloride, benazeprile.g. as hydrochloride, letrozole, cyclosporine, rivastigmine e.g. astartrate, fluvastatin e.g. as sodium, celecoxib, cetirizine e.g. ashydrochloride, tolterodine e.g. as tartrate, voriconazole, eletriptane.g. as hydrobromide, pregabalin, sunitinib e.g. as malate andziprasidone e.g. as hydrochloride or a (or an alternative)pharmaceutically acceptable salt thereof, e.g. the HCl salt.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising furtherspecific APIs, for example 4-quinolinecarboxamide, 8-aminoquinoline,acyclovir, ALTU-135, apixaban, armodafinil, arzoxifene, asenapine,asimadoline, asoprisnil, bazedoxifene, belatacept, bendamustine e.g. asHCl, bifeprunox, binodenoson, brecanavir, brivaracetam, buprenorphine,canertinib, casopitant e.g. as mesylate, certolizumab pegol, cladribine,clazosentan, clevudine, clodronate, conjugated estrogens synthetic B,cyproterone, cytofab, dalbavancin, dapoxetine, darapladib, dasatinib,denagliptin, dienogest, doxepin, dronedarone, eculizumab, eltrombopag,elzasonan, enalapril, enzastaurin, eplivanserin, etaquine,ethynylcytidine, exenatide, farglitazar, gaboxadol, garenoxacin,gemcabene, glimepiride, combination of glimepiride and rosiglitazone,hydrocodone e.g. as bitartrate, combination of hydrocodone bitartrateand ibuprofen, indiplon, ixabepilone, lapatinib, lecozotan, lonafarnib,lorazepam, lubiprostone, lurasidone, maraviroc, merimepodib, mesalamine,mesopram, minodronate, motivizumab, muraglitazar, nalmefene, naltrexone,naveglitazar, odiparcil, ONO-2506, ONO-8025, orexin-RA-1, oxycodone,pazopanib, pertuzumab, pexelizumab, pleconaril, polyphenon E,posaconazole, prasugrel, pruvanserin, ribavirin, rimonabant,roflumilast, roflumilast, ruboxistaurin e.g. as mesylate, saredutant,satraplatin, saxagliptin, seletracetam, silodosin, sitafloxacin,sitagliptin, solabegron, solifenacin e.g. as succinate, soraprazan,telbivudine, teriflunomide, tesaglitazar, ticlimumab, varenicline e.g.as tartrate, vicriviroc, vildagliptin, vinflunine, vorinostat,xaliprodene, sibutramine e.g. as hydrochloride, miglustat, tamsulosine.g. as hydrochloride, esomeprazole e.g. as magnesium, stavudine,amprenavir, thalidomide, lenalidomide, emtricitabine, dutasteride,itraconazole, indinavir e.g. as sulfate, aprepitant, orlistat,ganciclovir, oseltamivir e.g. as phosphate, nifedipine, temozolomide anddextroamphetamine e.g. as sulfate or a (or an alternative)pharmaceutically acceptable salt thereof, e.g. the HCl salt.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising solidAPIs that may be poorly water-soluble, such as for example antipyreticanalgesic agents such as benzoic acid, quinine, calcium gluconate,dimercaprol, sulfamine, theobromine, riboflavin, mephenesin,phenobarbital, thioacetazone, quercetin, rutin, salicylic acid,pyrabital, irgapyrin, digitoxin, griseofulvin, phenacetin, nervoussystem drug, sedation narcotics, muscle relaxant, hypotensive agent,antihistamines, antibiotics such as acetylspiramycin, erythromycin,kitasamycin, chloramphenicol, nystatin, colistin e.g. as sulfate,steroid hormones such as methyltestosterone, progesterone, estradiolbenzoate, ethinylestradiol, deoxycorticosterone acetate, cortisone e.g.as acetate, hydrocortisone, prednisolone, non-steroid yolk hormones suchas dienestrol, diethylstilbestrol, chlorotrianisene, other lipid solublevitamins, and where appropriate (other) pharmaceutically acceptable acidor base addition salts thereof (e.g. those salts which are in commonusage) and other such pharmaceutically active ingredients described inEuropean Pharmacopoeia, 3^(rd) Edition and one, two or more of them incombination.

In one embodiment of the invention the API is selected from acebutololHCl, fluoxetine HCl, paracetamol, sodium valproate, ketoprofen andmetformin HCl.

In one embodiment of the invention the API is not acebutolol HCl,fluoxetine HCl, paracetamol, sodium valproate, ketoprofen or metforminHCl.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprisingexcipients or other ingredients usable in e.g. pharmaceutical industry,such as for example L-asparagic acid, wheat gluten powder, acaciapowder, alginic acid, alginate, alfa-starch, ethyl cellulose, casein,fructose, dry yeast, dried aluminum hydroxide gel, agar, xylitol, citricacid, glycerin, sodium gluconate, L-glutamine, clay, croscarmellosesodium, Nymcel™, sodium carboxymethyl cellulose, crospovidone, calciumsilicate, cinnamon powder, crystalline cellulose-carmellose sodium,synthetic aluminum silicate, wheat starch, rice starch, potassiumacetate, cellulose acetate phthalate, dihydroxyaluminum aminoacetate,2,6-dibutyl-4-methylphenol, dimethylpolysiloxane, tartaric acid,potassium hydrogen tartrate, magnesium hydroxide, calcium stearate,magnesium stearate, purified shellac, purified sucrose, D-sorbitol, skimmilk powder, talc, low substitution degree hydroxypropylcellulose,dextrin, powdered tragacanth, calcium lactate, lactose, sucrose, potatostarch, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate,glucose, partially pregelatinized starch, pullulan, powdered cellulose,pectin, polyvinylpyrrolidone, maltitol, maltose, D-mannitol, anhydrouslactose, anhydrous calcium hydrogenphosphate, anhydrous calciumphosphate, magnesium aluminometasilicate, methyl cellulose, aluminummonostearate, glyceryl monostearate, sorbitan monostearate, medicinalcarbon, granular corn starch, dl-malic acid and possibly other suchothers classified as excipient in Arthur H. Kibbe: Handbook ofPharmaceutical Excipients, 3^(rd) Edition, and one, two or more of themin combination.

The method of the present invention may be applicable to producinggranules and tablets of the invention from material comprisingdisintegrants such as for example carboxymethyl cellulose, Nymcel™,sodium carboxymethyl cellulose, croscarmellose sodium, cellulose such aslow substitution degree hydroxypropylcellulose, (non-pregelatinized)starch such as sodium carboxymethyl starch, hydroxypropyl starch, ricestarch, wheat starch, potato starch, maize starch, partly pregelatinizedstarch and others classified as disintegrators in Arthur H. Kibbe:Handbook of Pharmaceutical Excipients, 3^(rd) Edition, and one, two ormore of them in combination. Favoured disintegrants include starch (egmaize starch) and/or carboxymethylcellulose.

The method of the present invention may be applicable to producinggranules and tablets of the invention from material comprising binderssuch as for example synthetic polymers such as crospovidone, saccharidessuch as sucrose, glucose, lactose and fructose, sugar alcohols such asmannitol, xylitol, maltitol, erythritol, sorbitol, water-solublepolysaccharides such as celluloses such as crystalline cellulose,microcrystalline cellulose, powdered cellulose, hydroxypropylcelluloseand methyl cellulose, starches, synthetic polymers such aspolyvinylpyrrolidone, inorganic compounds such as calcium carbonate andothers classified as binders in Arthur H. Kibbe: Handbook ofPharmaceutical Excipients, 3rd Edition, and one, two or more of them incombination. A favoured binder is microcrystalline cellulose.

Examples of fluidizing agents include silicon compounds such as silicondioxide hydrate, light silicic anhydride and others classified asfluidizing agents in Arthur H. Kibbe: Handbook of PharmaceuticalExcipients, 3rd Edition, and one, two or more of them in combination.

The method of the present invention may also be applicable to producegranules from any powder material other than an API or pharmaceuticalexcipient. The method may thus be applicable to e.g. any detergent,nutritive substance, sweetener, artificial or natural flavor, vitamin,herb, kampo medicine, spice, drink substance (e.g. coffee, cocoa, tea).Improvements over prior art may be achieved e.g. in the properties ofgranules or tablets made of such granules. For example, longer shelflife or quicker dissolution to water may be achieved.

Granulate mass produced according to the method of the invention mayhave one or more of the following desirable properties: substantialabsence of solid bridged between particles, good homogeneity, goodflowability, good compressibility, good tabletability.

Granulate mass prepared according to the invention from a mixture ofmaterials (eg with different particle sizes) surprisingly tends to bevery homogeneous suggesting that the method of the invention iseffective at countering any tendency for the materials to segregate (bycontrast with what would be expected if fractionation were performedusing sieves or other classifying means whose operation is based onfractionating material on the basis of the particle size, for example).

Tablets produced according to the method of the invention may have oneor more of the following desirable properties: good homogeneity, hightensile strength, fast disintegration time, high drug loading, need foronly a low amount of lubricant.

Some embodiments of the invention are described herein, and furtherapplications and adaptations of the invention will be apparent to thoseof ordinary skill in the art.

Certain Specific Embodiments A: Low Drug Low Tablets

When producing granular mass and tablets of material comprising only asmall proportion of active pharmaceutical ingredient, segregation ofgranular mass as well as content uniformity of resulting tablets maybecome serious issues. For example, it may be difficult to mix a largeproportion of excipient with a small proportion of API in powder formfor granulation in a manner that guarantees sufficiently low degree ofsegregation. If segregation occurs before tableting, the contentuniformity of the tablets may not be at sufficient level.

The invention also provides an improved method and apparatus for drygranulation which is highly suitable for preparing tablets having a lowamount of API. The method may be applicable to a wide variety of APIs.

Specifically, we have found a method for making tablets having a drugload of less than 20% utilizing a dry granulation method that produceswell-flowing granules from various materials, including APIs andexcipients and their combinations. As the different granular massesproduced by the granulation method have similar flow characteristics,segregation issues of granular mass and content uniformity issues oftablets of prior art may be avoided.

According to various aspects of the invention, at least two batches ofpowder material are granulated separately and the resulting granules arethen mixed together and compressed into tablets. The first batchcontains the API and optionally some excipients. Further excipients andAPIs may be provided in the second (and possible additional) batch(es).The ratio between excipients to API ratio in the first batch is kept lowenough to prevent segregation of powders in the mass before granulation.

As an aspect of the invention, we provide a method for producing atablet comprising a first active ingredient in an amount of 0.01-19.99%w/w e.g. at least 0.01, 0.1 or 0.5% and less than 5%, 10% or 19.99% w/wand one or more additional active ingredients and excipients includingat least a binder in an amount of 80.01-99.99% w/w e.g. at least 80.01,90% or 95% and less than 99.99%, 99.9% or 99.5% w/w. The methodcomprises (i) preparing granules from a powder comprising activeingredient and optionally one or more accompanying excipients whereinthe ratio of excipients to active ingredient is less than 5:1, 4:1 or3:1 by a process characterized in that a compaction force is applied tothe powder to produce a compacted mass comprising a mixture of fineparticles and granules and separating and removing fine particles and/orsmall granules from the granules by entraining the fine particles and/orsmall granules in a gas stream and collecting the accepted granules (ii)preparing granules from a powder comprising one or more excipientsincluding at least a binder and optionally one or more second or furtheractive ingredients by a process characterized in that a compaction forceis applied to the powder to produce a compacted mass comprising amixture of fine particles and granules and separating and removing fineparticles and/or small granules from the granules by entraining the fineparticles and/or small granules in a gas stream and collecting theaccepted granules (iii) blending the accepted granules of step (i) andstep (ii) with each other and with any other components of the tablet ingranular or fine powder form; and (iv) compressing the blend to form atablet.

Another aspect of the invention is a method for producing a tabletcomprising (a) a first active ingredient in an amount of 0.01-19.99% w/we.g. at least 0.01, 0.1 or 0.5% and less than 5%, 10% or 19.99% w/w and(b) one or more excipients including at least a binder in an amount of80.01-99.99% w/w e.g. at least 80.01, 90% or 95% and less than 99.99%,99.9% or 99.5% w/w. The method comprises (i) preparing granules from apowder comprising active ingredient and no excipients by a processcharacterized in that a compaction force is applied to the powder toproduce a compacted mass comprising a mixture of fine particles andgranules and separating and removing fine particles and/or smallgranules from the granules by entraining the fine particles and/or smallgranules in a gas stream and collecting the accepted granules (ii)preparing granules from a powder comprising one or more excipientsincluding at least a binder and optionally one or more second or furtheractive ingredients by a process characterized in that a compaction forceis applied to the powder to produce a compacted mass comprising amixture of fine particles and granules and separating and removing fineparticles and/or small granules from the granules by entraining the fineparticles and/or small granules in a gas stream and collecting theaccepted granules (iii) blending the accepted granules of step (i) andstep (ii) with each other and with any other components of the tablet ingranular or fine powder form; and (iv) compressing the blend to form atablet.

The one or more excipients of step (ii) of the above aspects of theinvention may include a disintegrant.

The granules in step (ii) of the above aspects of the invention may beprepared from a powder also comprising a disintegrant.

Suitably in step (ii) granules are prepared from a powder comprising allthe components of the tablet formulation except said first activeingredient, said optional accompanying excipients and lubricant and instep (iii) the accepted granules of steps (i) and (ii) are blended withlubricant.

The ratio of binder to disintegrant may be e.g. between 10:1 and 1:1w/w, suitably around 4:1.

In some embodiments, the granules of step (i), step (ii) or step (iii)may comprise more than 1, 2 or 5 percent and up to 30, 20 or 10 percent(weight) of e.g. metholose or hypromellose (hydroxypropylmethylcellulose) to control the disintegration and dissolution time ofthe tablet. The dissolution time of such tablet may be e.g. at least0.5, 1, 4 or 8 hours in the gastric system.

A lubricant may, for example, be selected from magnesium stearate andhydrogenated plant or vegetable oil eg hydrogenated cottonseed oil orany other suitable lubricant known to a person skilled in the art.

In tablets of the invention a relatively low amount of lubricant eg0.1-5% eg 0.1-0.5% w/w may be employed.

The first, second or further active ingredient may be sensitive tomoisture (e.g. ambient humidity), heat or compression forces.Alternatively or additionally, the active ingredient may be insoluble inwater.

When manufacturing low drug-load tablets from APIs that are especiallysensitive to e.g. compression, heat or moisture (e.g. ambient humidity),the API may be granulated together with one or more excipients thatprotect the API during the granulating and/or tableting processes. Forexample, nicorandil is known as an API that is sensitive to at leastambient humidity. Additionally, nicorandil may also be sensitive to heatand/or compression forces typically used in granulation and tabletingprocesses of prior art.

An embodiment of the invention may thus be a tablet manufactured usingthe method of the first aspect of this aspect of the invention whereinthe first active ingredient is nicorandil. A first batch of powdermaterial comprising the API is prepared. In the first batch, somemoisture absorbing excipient, e.g. maize starch and/or hypromellose maybe mixed with the API to protect the API from ambient humidity. Further,to protect the API from effect of compression forces used ingranulation, some well-compressible excipient, e.g. microcrystallinecellulose may be mixed with the API and other excipients. Suitably, theratio of excipients to API is 5:1 or less in the first batch. Then firstbatch of powder material is granulated according to step (i) of thefirst aspect of the invention disclosed herein.

Separately, a second batch of material comprising at least binder, e.g.microcrystalline cellulose and optionally other excipients, e.g.disintegrant, e.g. maize starch or carboxymethylcellulose, is mixed andgranulated according to step (ii) of the first aspect of the invention.Finally, the two batches of granulated material are mixed together alongwith some lubricant, e.g. magnesium stearate or hydrogenated cottonseedoil, and the resulting bulk is compressed into tablets.

B: High Drug Low Tablets

There is also provided an improved method and apparatus for drygranulation which is highly suitable for preparing tablets having a highAPI content, high tensile strength and a suitable disintegrationprofile. The method may be applicable to a wide variety of APIs.

Specifically, we have found a method for making tablets having a drugload of at least 50% and less than 90% utilizing a dry granulationmethod that produces well-flowing granules from various materials,including APIs and excipients and their combinations.

A compaction force is used to produce granules from material thatcomprises binder excipient and optionally at least one active ingredientand one or more other excipients. Suitably the compaction force forcompacting binder excipient is low to preserve a high level of bindingcapabilities of the binder for the tableting phase.

An aspect of the invention is a method for producing a tablet comprising(a) at least one active ingredient in a combined amount of 50-90% w/we.g. at least 50%, 51%, 60% or 70% and less than 80%, 89% or 90% w/wsuch as 51-89% w/w and (b) one or more excipients including at least abinder in an amount of 10-50% w/w e.g. at least 10%, 11% or 20% and lessthan 30%, 40%, 49% or 50% w/w such as 11-49% w/w. The method comprisessteps of (i) preparing granules from a powder comprising a binder andoptionally one or more other excipients or active ingredients by aprocess characterized in that a compaction force is applied to thepowder to produce a compacted mass comprising a mixture of fineparticles and granules and separating and removing fine particles and/orsmall granules from the granules by entraining the fine particles and/orsmall granules in a gas stream and collecting the accepted granules (ii)optionally blending the accepted granules with other components of thetablet in granular or fine powder form; and (iii) compressing thegranules or blend to form a tablet; with the proviso that the tabletdoes not comprise (a) paracetamol, maize starch and microcrystallinecellulose in a ratio of 60:20:20 w/w, (b) acebutolol HCl and starch in aratio of 90:10 w/w, (c) sodium valproate, hypromellose and maize starchin a ratio of 90:5:5 w/w, (d) ketoprofen and maize starch in a ratio of50:50 w/w or (e) metformin HCl, microcrystalline cellulose and maizestarch in a ratio of 80:14:6 w/w.

The granules of step (i) may be prepared from a powder also comprising adisintegrant.

The granules of step (i) may also be prepared from a powder alsocontaining an active ingredient.

Suitably the binder content of the powder of step (i) is 5% or more eg6% or more e.g. 10% or more w/w.

In some embodiments, granules may be prepared in step (i) from a powdercomprising all the components of the tablet formulation except lubricantand in step (ii) the accepted granules are blended with lubricant.

In some embodiments, at least one other component of the tabletformulation may be in granular form in step (ii) and is prepared from apowder comprising another component by a process characterized in that acompaction force is applied to the powder to produce a compacted masscomprising a mixture of fine particles and granules and separating andremoving fine particles and/or small granules from the granules byentraining the fine particles and/or small granules in a gas stream. Theother component of the tablet formulation may also comprise an activeingredient.

In some embodiments, the active ingredient may be e.g. moisturesensitive, heat sensitive or insoluble in water.

Yet another aspect of the invention is a method for preparing granulesfrom a powder comprising (a) active ingredient in an amount of 50-90%e.g. at least 50%, 51%, 60% or 70% and less than 80%, 89% or 90% w/wsuch as 51-89% w/w and (b) one or more excipients including at least abinder in an amount of 10-50% w/w e.g. at least 10%, 11% or 20% and lessthan 30%, 40%, 49% or 50% w/w such as 11-49% w/w by a processcharacterized in that a compaction force is applied to the powder toproduce a compacted mass comprising a mixture of fine particles andgranules and separating and removing fine particles and/or smallgranules from the granules by entraining the fine particles and/or smallgranules in a gas stream wherein the powder does not comprise (a)paracetamol, maize starch and microcrystalline cellulose in a ratio of60:20:20 w/w, (b) acebutolol HCl and starch in a ratio of 90:10 w/w, (c)sodium valproate, hypromellose and maize starch in a ratio of 90:5:5 w/wor (d) ketoprofen and maize starch in a ratio of 50:50 w/w.

The ratio of binder to disintegrant may be e.g. between 10:1 and 1:1w/w, suitably around 4:1.

In some embodiments, the granules of step (i) or step (ii) may comprisemore than 1, 2 or 5 percent and up to 30, 20 or 10 percent (weight) ofe.g. metholose or hypromellose (hydroxypropyl methylcellulose) tocontrol the disintegration and dissolution time of the tablet. Thedissolution time of such tablet may be e.g. at least 0.5, 1, 4 or 8hours in the gastric system.

A lubricant may, for example, be selected from magnesium stearate andhydrogenated plant or vegetable oil eg hydrogenated cottonseed oil orany other suitable lubricant known to a person skilled in the art.

In tablets of the invention a relatively low amount of lubricant eg0.1-5% eg 0.1-0.5% w/w may be employed.

The active ingredient(s) may be sensitive to moisture (e.g. ambienthumidity), heat or compression forces. Alternatively or additionally,the active ingredient may be insoluble in water.

C: Very High Drug Load Tablets

Very high drug load in combination with good tensile strength andsuitable disintegration profile is often difficult to achieve in atablet using traditional formulation techniques. It is especiallychallenging to achieve a combination of sufficient tensile strength witha disintegration profile suitable to the API.

The invention provides an improved method and apparatus for drygranulation which is suitable for preparing tablets having a very highAPI content, sufficient tensile strength and a suitable disintegrationprofile. The method may be applicable to a wide variety of APIs.

Specifically, we have found a method for making tablets having a drugload of at least 90% and less than 100% utilizing a dry granulationmethod that produces well-flowing granules from various materials,including APIs and excipients and their combinations.

A compaction force is used to produce granules from material thatcomprises at least one active pharmaceutical ingredient and optionallyone or more excipients. Suitably the compaction force for compacting theactive pharmaceutical ingredient is low to preserve a sufficient levelof binding capabilities of the active ingredient for the tabletingphase.

According to an aspect of the invention, we provide a method forproducing a tablet comprising (a) active ingredient in an amount90.01-99.99% w/w and (b) one or more excipients in an amount 0.01-9.99%w/w which comprises (i) preparing granules from a powder comprising atleast the active ingredient and optionally one or more excipients by aprocess characterized in that a compaction force is applied to thepowder to produce a compacted mass comprising a mixture of fineparticles and granules and separating and removing fine particles and/orsmall granules from the granules by entraining the fine particles and/orsmall granules in a gas stream and collecting the accepted granules (ii)optionally blending the accepted granules with other components of thetablet in granular or fine powder form; and (iii) compressing thegranules or blend to form a tablet, which tablet does not containibuprofen sodium dihydrate in an amount 95% w/w as active ingredient.

The granules of step (i) may prepared from a powder also comprising abinder.

The granules of step (i) may also be prepared from a powder alsocomprising a disintegrant.

The granules of step (i) may be prepared from a powder comprising allthe components of the tablet formulation except lubricant and in step(ii) the accepted granules are blended with lubricant.

In some embodiments, the granules of step (i) or step (ii) may comprisemore than 1, 2 or 5 percent and up to 30, 20 or 10 percent (weight) ofe.g. metholose or hypromellose (hydroxypropyl methylcellulose) tocontrol the disintegration and dissolution time of the tablet. Thedissolution time of such tablet may be e.g. at least 0.5, 1, 4 or 8hours in the gastric system.

In some embodiments, the tablet may comprise (a) active ingredient in anamount 91-99% w/w and (b) one or more excipients in an amount 1-9% w/w.

In some embodiments, the active ingredient may be moisture sensitive,heat sensitive or insoluble in water.

Yet another aspect of the invention is a method for preparing granulesfrom a powder comprising (a) active ingredient in an amount 90.01-99.99%w/w and (b) one or more excipients in an amount 0.01-9.99% w/w by aprocess characterized in that a compaction force is applied to thepowder to produce a compacted mass comprising a mixture of fineparticles and granules and separating and removing fine particles and/orsmall granules from the granules by entraining the fine particles and/orsmall granules in a gas stream.

Suitably the active ingredient is not ibuprofen sodium dihydrate.

D: Tablets Containing Excipients

Some excipients, e.g. binders, are known to maintain theirtablettability and other characteristics the better, the less thematerial is compacted in the granulation process.

However, lightly compacted granules may be very fragile and the bulk maycontain a large proportion of fine particles. Sieving techniques used intraditional dry granulation processes are not generally suitable forproducing well-flowing granular mass from such material as the sievesmay clog and the fragile granules may be destroyed in the sievingprocess. Furthermore, lightly compacted excipient granules of prior arttypically have flowability issues that make their use in tabletmanufacturing process difficult e.g. because of segregation in themanufacturing process.

The invention provides an improved method and apparatus for drygranulation which is highly suitable for preparing tablets usingexcipients that preserve their useful properties during the granulationand tableting phases. The method may be applicable to tablets containingAPI selected from a wide variety of APIs.

Specifically, we have found a method for making tablets using drygranulated well-flowing and easily tabletable excipients. The drygranulated excipient granules of the method have flow characteristicsthat are similar to the flow characteristics of granules made of e.g.active pharmaceutical ingredients. Prior to mixing with the granularexcipients, the active ingredients may be granulated separately using asuitable granulation method, including the method used for granulatingthe excipients.

An aspect of the invention is a method for producing a tablet comprising(a) active ingredient and (b) one or more excipients including at leasta binder which comprises (i) preparing granules from a powder comprisingone or more excipients including at least a binder and not comprisingany active ingredient by a process characterized in that a compactionforce is applied to the powder to produce a compacted mass comprising amixture of fine particles and granules and separating and removing fineparticles and/or small granules from the granules by entraining the fineparticles and/or small granules in a gas stream and collecting theaccepted granules (ii) blending the accepted granules with othercomponents of the tablet, including the active ingredient, in granularor fine powder form; and (iii) compressing the blend to form a tablet.This aspect of the invention contains a proviso that the tablet does notcomprise metformin HCl, maize starch and microcrystalline cellulose in aratio of 80:6:14 w/w.

The one or more excipients of step (i) may be selected fromdisintegrants and binders.

The one or more excipients in step (ii) may be in granular form and isprepared from a powder comprising another component by a processcharacterized in that a compaction force is applied to the powder toproduce a compacted mass comprising a mixture of fine particles andgranules and separating and removing fine particles and/or smallgranules from the granules by entraining the fine particles and/or smallgranules in a gas stream.

The other component of the tablet formulation may comprise an activeingredient.

The powder of step (i) may comprise a disintegrant.

The powder of step (i) may comprise a binder and a disintegrant whereinthe ratio of binder to disintegrant is between 10:1 and 1:1 w/w.

Suitably, the ratio of binder to disintegrant is between around 3.1:1and 4.9:1 eg around 4:1 w/w.

In some embodiments, the binder may be microcrystalline cellulose andthe disintegrant may be starch e.g. maize starch.

In some embodiments, the granules of step (i) or step (ii) may comprisemore than 1, 2 or 5 percent and up to 30, 20 or 10 percent (weight) ofe.g. metholose or hypromellose (hydroxypropyl methylcellulose) tocontrol the disintegration and dissolution time of the tablet. Thedissolution time of such tablet may be e.g. at least 0.5, 1, 4 or 8hours in the gastric system.

Another component of the tablet in step (ii) may be a lubricant.

In some embodiments, the tablet may comprise 50-90% w/w activeingredient, the balance being one or more excipients. In some otherembodiments, the tablet may comprise 0.01-19.99% w/w active ingredient,the balance being one or more excipients.

The active ingredient of the tablet may be moisture sensitive, heatsensitive or insoluble in water.

Yet another aspect of the invention is a method for preparing granulesfrom a powder comprising one or more excipients and not comprising anyactive ingredient by a process characterized in that a compaction forceis applied to the powder to produce a compacted mass comprising amixture of fine particles and granules and separating and removing fineparticles and/or small granules from the granules by entraining the fineparticles and/or small granules in a gas stream wherein the powder doesnot comprise maize starch and microcrystalline cellulose in a ratio of3:7 w/w.

In one embodiment, the method for preparing granules disclosed herein isapplied to granulating powder comprising pure excipient, i.e. singleexcipient material having purity of at least 95%, 98% or 99%.

E: Tablets Comprising Metformin

Metformin is a widely used API for treatment of diabetes. It has provento be a quite challenging API to formulate, especially if a high drugload together with suitable disintegration is needed. Further, combiningmetformin with other APIs into a single high drug load tablet is alsoregarded as a difficult task.

The invention provides an improved method and apparatus for drygranulation which is highly suitable for preparing tablets comprisingmetformin and at least one second active ingredient. The tablets mayhave a high API content, high tensile strength and a suitabledisintegration profile.

Specifically, we have found a method for making tablets having a drugload of at least 50% and less than 90% utilizing a dry granulationmethod that produces well-flowing granules from various materials,including APIs and excipients and their combinations.

A compaction force is used to produce granules from material thatcomprises binder excipient and optionally at least one active ingredientand one or more other excipients. The compaction force for compactingbinder excipient is suitably adapted to be low to preserve a high levelof binding capabilities of the binder for the tableting phase.

An aspect of the invention is a method for producing a tablet comprising(a) metformin and at least one second active ingredient in a combinedamount of 50-90% w/w e.g. at least 50%, 60% or 70% and less than 90% or80% w/w and (b) one or more excipients including at least a binder in anamount of 10-50% w/w e.g. at least 10% or 20% and less than 50%, 40% or30% w/w. The method comprises steps of (i) preparing granules from apowder comprising a binder and optionally one or more other excipientsor active ingredients by a process characterized in that a compactionforce is applied to the powder to produce a compacted mass comprising amixture of fine particles and granules and separating and removing fineparticles and/or small granules from the granules by entraining the fineparticles and/or small granules in a gas stream and collecting theaccepted granules (ii) optionally blending the accepted granules withother components of the tablet in granular or fine powder form; and(iii) compressing the granules or blend to form a tablet.

As used herein “metformin” includes metformin and pharmaceuticallyacceptable salts thereof. Most suitably metformin is employed as its HClsalt.

The at least one second active pharmaceutical ingredient may be selectede.g. from any meglitinide, e.g. repaglinide or nateglinide, anyintestinal alpha-glucosidase inhibitor, e.g. acarbose, sibutramine, anycannabinoid receptor antagonist, and bupropion. Said active ingredientsmay be employed in the from of pharmaceutically acceotable salts.

Metformin and the second active pharmaceutical ingredient may begranulated separately or together.

The granules of step (i) may be prepared from a powder also comprising adisintegrant.

The granules of step (i) may also be prepared from a powder alsocontaining an active ingredient. For example said active ingredient maybe metformin. Alternatively it may be the second active ingredient.

In some embodiments, granules may be prepared in step (i) from a powdercomprising all the components of the tablet formulation except lubricantand in step (ii) the accepted granules are blended with lubricant.

In some embodiments, at least one other component of the tabletformulation may be in granular form in step (ii) and is prepared from apowder comprising another component by a process characterized in that acompaction force is applied to the powder to produce a compacted masscomprising a mixture of fine particles and granules and separating andremoving fine particles and/or small granules from the granules byentraining the fine particles and/or small granules in a gas stream. Theother component of the tablet formulation may also comprise an activeingredient.

In some embodiments, the active ingredient may be e.g. moisturesensitive, heat sensitive or insoluble in water.

Yet another aspect of the invention is a method for preparing granulesfrom a powder comprising (a) metformin and at least one second activeingredient in a combined amount of 50-90% w/w e.g. at least 50%, 60% or70% and less than 90% or 80% w/w and (b) one or more excipientsincluding at least a binder in an amount of 10-50% w/w e.g. at least 10%or 20% and less than 50%, 40% or 30% w/w by a process characterized inthat a compaction force is applied to the powder to produce a compactedmass comprising a mixture of fine particles and granules and separatingand removing fine particles and/or small granules from the granules byentraining the fine particles and/or small granules in a gas stream.

The ratio of binder to disintegrant may be e.g. between 10:1 and 1:1w/w, suitably around 4:1.

In some embodiments, the granules of step (i) or step (ii) may comprisemore than 1, 2 or 5 percent and up to 30, 20 or 10 percent (weight) ofe.g. metholose or hypromellose (hydroxypropyl methylcellulose) tocontrol the disintegration and dissolution time of the tablet. Thedissolution time of such tablet may be e.g. at least 0.5, 1, 4 or 8hours in the gastric system.

A lubricant may, for example, be selected from magnesium stearate andhydrogenated plant or vegetable oil eg hydrogenated cottonseed oil orany other suitable lubricant known to a person skilled in the art.

In tablets of the invention a relatively low amount of lubricant eg0.1-5% eg 0.1-0.5% w/w may be employed.

The active ingredient(s) may be sensitive to moisture (e.g. ambienthumidity), heat or compression forces. Alternatively or additionally,the active ingredient may be insoluble in water.

Aspects Relating to Specific Embodiments A to E

The disintegrant may for example be selected from carboxymethylcellulose, Nymcel™, sodium carboxymethyl cellulose, croscarmellosesodium, cellulose such as low substitution degreehydroxypropylcellulose, starch such as sodium carboxymethyl starch,hydroxypropyl starch, rice starch, wheat starch, potato starch, maizestarch, partly pregelatinized starch and others classified asdisintegrants in Arthur H. Kibbe: Handbook of Pharmaceutical Excipients,3^(rd) Edition, and one, two or more of them in combination.

Suitably, the disintegrant is starch (e.g. maize starch) orcarboxymethylcellulose.

The binder may for example be selected from synthetic polymers such ascrospovidone, saccharides such as sucrose, glucose, lactose andfructose, sugar alcohols such as mannitol, xylitol, maltitol,erythritol, sorbitol, water-soluble polysaccharides such as cellulosessuch as crystalline cellulose, microcrystalline cellulose, powderedcellulose, hydroxypropylcellulose and methyl cellulose, starches,synthetic polymers such as polyvinylpyrrolidone, inorganic compoundssuch as calcium carbonate and others classified as binders in Arthur H.Kibbe: Handbook of Pharmaceutical Excipients, 3rd Edition, and one, twoor more of them in combination.

Suitably, the binder is microcrystalline cellulose.

The method may typically be run as a continuous process.

Suitably the process is carried out in the substantial absence ofliquid.

A further aspect of the invention is a tablet obtainable according tothe methods of specific embodiments A to E.

Still yet another aspect of the invention is a dry granulate massobtainable according to the method of preparing granules according tothe methods of specific embodiments A to E.

BRIEF DESCRIPTION OF DRAWINGS

In the following, the invention is illustrated, but in no way limited byreference to the accompanying drawings in which

FIG. 1 a and FIG. 1 b show exemplary apparatus according to anembodiment of the invention,

FIG. 2 a shows use of roller compactor according to an embodiment of theinvention,

FIG. 2 b shows use of roller compactor producing both avoidable dense(according to prior art) and desirable porous granules,

FIG. 2 c shows an example of a granule produced by a method of priorart.

FIG. 2 d shows an example of a granule according to an embodiment of theinvention.

FIG. 2 e shows another example of granules according to an embodiment ofthe invention,

FIG. 2 f shows yet another example of granules according to anembodiment of the invention,

FIG. 2 g illustrates an example about formation of granular mass of anembodiment of the present invention,

FIG. 2 h shows particle size distribution diagrams of materials shown inFIG. 2 g,

FIG. 2 i shows particle size distribution diagrams of material processedusing an embodiment according to FIGS. 1 a and 3,

FIG. 2 j shows surface images of granules produced using different lowcompaction forces according to embodiments of the present invention,

FIG. 3 a shows an exemplary fractionating device according to anembodiment of the invention,

FIG. 3 b shows another exemplary fractionating device contemplated bythe inventors,

FIG. 3 c shows yet another exemplary fractionating device contemplatedby the inventors,

FIG. 4 shows an exemplary fractionating device that contains anadditional rotating device usable according to an embodiment of theinvention,

FIG. 5 a and FIG. 5 b show two alternative exemplary cylindricalcomponents that can be used in the fractionating device shown in FIG. 4,

FIG. 5 c shows an exemplary perforated steel sheet that may be used aspart of a rotating device according to an embodiment of the presentinvention,

FIG. 6 shows an exemplary dual-filter arrangement for enablingcontinuous operation of the system of an embodiment of the presentinvention,

FIG. 7 shows an exemplary arrangement for monitoring and adjusting thecharacteristics of the accepted granules in real time,

FIG. 8 shows an exemplary arrangement for mixing granulate masses fromseparately compacted substances, and

FIG. 9 shows an exemplary device for determining flowability of a powderor granulate mass.

DETAILED DESCRIPTION OF DRAWINGS

The apparatus 100 (FIGS. 1 a and 1 b) of an embodiment of the inventioncomprises a compacting device that compacts powder material intogranules and a fractionating device that fractionates at least some fineparticles and/or small granules away from acceptable granules. Twodifferent alternatives for a fractionating device are shown in FIGS. 1 aand 1 b. The fractionating device 112 in FIG. 1 a is shown in moredetail in FIG. 3 a. The fractionating device 112 in FIG. 1 b is shown inmore detail in FIG. 4. The apparatus shown in FIG. 1 a and FIG. 1 bcomprise a raw material feeding container 101, into which material to begranulated is fed. The feeding container is connected to a pneumaticconveyor pipeline 102, to which the material is passed through a feedervalve 103. The tubes of the pneumatic conveyor system have a diameter ofabout 47 mm and their material may be for example some suitable plasticmaterial, e.g. polyethene. The feeder valve may be a so-calledstar-shape flap valve. One such valve is manufactured by Italianpharmaceutical device manufacturer CO.RA™ (Lucca, Italy). In operation,the closing element of the valve may be turned 180° alternately ineither direction, whereby buildup of the powder substance in thecontainer can be avoided. Other equipment intended for continuouscharging of powder substance, such as compartment feeders, may also beused.

The pressure of the air flowing within the conveyor 102 may be adjustedto be lower than that of the surroundings. This may be achieved forexample using an extractor suction fan 104. The suction fan is of makeBUSCH™ (Maulburg, Germany) and model Mink MM 1202 AV. The fan may beoperated for example at 1860 RPM. Makeup carrier gas may be suppliedthrough a connection 105. The material fed from the feeding container istransported through the conveyor 102 into a separating device 106,wherein fine rejected particles and new feed from container 101 areseparated from the carrier gas. The fan can be provided with filters(shown in FIG. 6) situated beside the separating device. The device maybe capable of continuous operation. One such device is a cyclone. Afterthe separating step, the separated powder falls into an intermediatevessel 107.

The container 107 can be mounted on load cells 108 to measure the weightof the material. The intermediate vessel 107 is provided with valves 109a and 109 b which may be of the same type as the feeding container valve103. From the intermediate vessel 107, the powder is transferred to acompacting device, e.g. roller compactor 110 to produce a ribbon ofcompacted material which is then passed to a flake crushing screen 111where granules are created by crushing the ribbon. In the context ofthis invention, compacting is considered as the step of the process thatproduces granules to be fractionated, regardless of whether a separatescreen or milling device 111 is used or not. The compaction force of thecompactor 110 may be adjusted by e.g. altering the feed rate of thepowder substance, the rotating speed of the rolls of the rollercompactor, the pressure applied to the rolls of the compactor deviceand/or the thickness of the resulting ribbon. The compaction forceapplied by the compactor may be adjusted to a low level to achieve thedesired properties of the compacted mass, e.g. the porosity of theresulting granules and/or proportion of fine particles and/or smallgranules. The compactor and the flake crushing screen are devices wellknown to a person skilled in the art. After passing the compacting andflake crushing devices, the material is partially in the form ofgranules, but part of the material will still be in the form of fineparticles and/or small granules. The maximum size of the granules aswell as the mean size of the granules may be affected by, for example,the mesh size of the flake crushing screen. It should be noted, however,that size of a granule may increase as result of agglomeration in thefractionating and/or conveying steps of the process.

In some embodiments (not shown in figure), the apparatus 100 maycomprise more than one compacting device, e.g. roller compactor, toimprove e.g. capacity and/or continuous processing capabilities of theapparatus. The compacting devices may require some periodic servicebreaks e.g. for cleaning up. The apparatus 100 may continue operationeven if one of the compacting devices is being serviced.

The product from the above steps that contains fine particles and porousgranules and that may be statically charged (e.g. bytriboelectrification) is conveyed to a fractionating chamber 112. Theremay be one or two e.g. star-shaped flap valves between compacting deviceand fractionating device to control the flow of compacted material tothe fractionating device. The fractionating device divides the granulatemass into an accepted fraction and a rejected fraction on the basis ofhow different particles of the mass are affected by the carrier gasstream that flows in the fractionating device. The rejected fractionpasses with the fed carrier gas stream to the feed conveyor 102, forre-processing, and the accepted fraction is led into a product container113. By this means the product granules are treated gently and arelatively large volume of material comprising mostly fine particlesand/or small granules is removed from the mass.

The operation of the fractionating chamber 112 is described in moredetail with reference to FIGS. 3-6. There are many possible alternativefractionating devices.

In the embodiments shown in FIG. 1 a and FIG. 1 b, load cells 108 arefitted to the container 107. Such sensors and other instrumentation canalso be arranged in other containers and components of the system. Notall of the possible instrumentation is shown in the figures. For examplethe pneumatic conveyor, if required, may be provided with at least onepressure difference sensor 114, the information from which can be usedto control the operation of the apparatus.

The present invention may also be carried out as a batch process wherethe reject fraction is not immediately returned to the system using theconveyor 102, but fed into a container of reject material. Such a systemis not described in detail, but its construction and use will be readilyapparent to those of skilled in the art.

The apparatus can be automated by transferring information received fromthe various sensors e.g. the pressure difference sensors 114, the loadcells 108 and the valves 103 as well as information regarding the speedof rotation and the loads of the motors to a control unit and byapplying appropriate control means 119. In some embodiments, the controlmeans may monitor and control the amount of material currently incirculation in various components of the apparatus. For example, thecontrol means may receive information from at least one of the loadcells (scales) 108, 117, 118 of the apparatus and control operation ofany of the valves 103, 109 a and 109 b according to the informationreceived from the load cells. Further, the operation of suction fan 104may be controlled e.g. according to information received from e.g.pressure difference sensor 114, from an instrument measuring gas flowrate or from any instrument measuring the properties, e.g. flowability,and/or amount of accepted granules.

In some embodiments where e.g. there is no control means 119, the valvesof the process, e.g. 103, 109 a and 109 b, may be operated using timersthat actuate a valve according e.g. to some suitable fixed or varyingtime interval.

Valves 109 a and 109 b may be operated so that flow of gas from thecontainer 107 through the valves to the compacting device 110 isessentially prevented. For example, the valves 109 a and 109 b may beoperated in an alternating manner so that at least one of the valves iskept closed at any given point of time during the operation of theapparatus 100. This way, the even gas flow in the fractionating andconveying parts of the process is not disturbed by any pressure shocks.

For enhancing flow of powder material in the process, some vibrating orultrasound emitting devices or other suitable means may be included e.g.in the components of the process where pneumatic conveying is not used.Such components may be e.g. the container 107, various parts of thecompacting device 110 and flake crushing (granulator) device 111.

Control of the compaction force of the compacting device, e.g. rollercompactor 110 is also useful, as granule structure as well as theproportion of fine particles and/or small granules is significantlyaffected by the compaction force used. The compaction force depends on anumber of parameters, such as the rotating speed of the rolls and thefeed rate of the powder substance. For example, the higher the feed rateof the powder substance for a given roller rotation rate, the higher thecompaction force will be.

The exemplary apparatuses of FIGS. 1 a and 1 b also comprise a receiverfilter 115 and a safety filter 116. The receiver filter is the primarymeans of filtering any particles away from the gas that exits thesystem. However, as the materials processed by the system may be e.g.toxic or otherwise hazardous, a separate safety filter arrangement isrequired in many cases. There are multiple solutions known to a personskilled in the art that may be possible for the filtering arrangement115 and 116. One receiver filter arrangement 115 suitable for e.g. anembodiment capable of continuous processing of powder material isdescribed in FIG. 6.

The material of the conveyor 102 may be e.g. PVC, e.g. FDA PVC. Variouscomponents of the system may be connected together with electric wiresfor grounding purposes. Suitably the entire system is grounded.

In FIG. 2 a the roller compactor 200 compacts the mass 203 containingraw material and optionally particles recycled from the fractionatingdevice into a ribbon 204, 205, 206 using rolls 201,202 that applymechanical force to the mass to be compacted. Depending on thecompaction force applied to the mass and the thickness of the ribbon,the amount of mass that gets compacted into granules 204, 205 varies.The remaining mass 206 may remain non-compacted or weakly compacted fineparticles and/or weakly compacted small granules for example in themiddle of the ribbon. The small granules and/or fine particles may notbe capable of forming acceptable granules alone. However, the presenceof such mass may have a positively contributing role in forming ofacceptable granules in the fractionating and/or conveying steps of theprocess e.g. through triboelectrification and electrostatic forces.Depending on the feed material and compacting parameters, such asthickness of the ribbon, the proportion of fine particles and/or smallgranules may vary.

A convenient way to adjust operating parameters of the system is to setthe compaction force of the roller compactor to the minimum thatproduces at least some well-flowing granules and set the rotating speed(see the description related to FIG. 4) of the fractionating device tothe maximum available (e.g. about 100 RPM) in the device of make ROTAB™(Donsmark Process Technology A/S, Denmark) and model 400EC/200 and thenadjust the carrier gas flow rate so that acceptable granules withdesired flow characteristics start flowing out the system. Too littlegas flow in the fractionating device causes the proportion of fineparticles and/or small granules to increase in the mass of acceptedgranules whereas use of too high a gas flow causes a large proportion ofacceptable granules to be unnecessarily re-processed. Setup of theoptimal gas flow may be done manually or automatically for example usingreal-time measurement of flow of accepted granules and characteristicsof those granules. One such measurement arrangement is shown in FIG. 7.

FIG. 2 b illustrates an example of the creation of unwanted densegranules and/or granules having solid bridges 210, 211 when a highcompaction force as in the prior art is used. The more dense granulesthere are in the mass, the lower the quality of the mass may be fortableting. Although the flow characteristics of the mass resulting fromusing prior art high compaction forces (or repeated compaction withlower forces) may be acceptable even without fractionating, thecompressibility and/or tabletability of the mass may with some materialsbe significantly lower, or some other characteristics of the tablet suchas disintegration time may be undesirable. Moreover, significant heatingof the material in the compaction step of prior art granulation processmay be observed leading for example to formation of solid bridgesthrough crystallization and/or degradation of components of the granulesor undesirable characteristics of the granulate mass. Yet further, useof high compaction force typically reduces the proportion of smallgranules and/or fine particles 206 in the resulting granulate mass. Toolow a percentage of such small granules and/or fine particles in thefractionating and/or conveying steps of the process may adversely affectthe quality of the resulting accepted granules.

FIG. 2 c shows a scanning electronic microscope (SEM) picture of anexemplary dense maize starch granule that is produced using highcompaction force (e.g. more than 80 kN using Hosokawa Bepex PharmapaktorL200/50P roll compactor) for maize starch (CERESTAR™ product code C*Gel03401, batch number SB4944) typical of the dry granulation methods ofthe prior art.

FIG. 2 d shows a picture of an exemplary porous starch granule of thesame starch that is produced using low compaction force (in this case,30-35 kN using the same Hosokawa roll compactor) and subsequentfractionation using gas stream according to an embodiment of the presentinvention. For different materials, the “low compaction force” thatproduces porous granules and “high compaction force” that producesunacceptable amount of dense granules and/or granules with solid bridgesmay vary. We have observed that the surface of the granule of FIG. 2 cis less porous (i.e more dense) than the granule of FIG. 2 d. There ismore free space (i.e. pores) between the individual particles in theporous granule of FIG. 2 d than in the dense granule of FIG. 2 c. Therealso seems to be larger proportion of loosely attached particles on thesurface of the porous granule of FIG. 2 d than in the dense granule ofFIG. 2 d. Further, the granule of FIG. 2 c has more edges than thegranule of FIG. 2 d. The round shape of the porous granule maycontribute to the good flow characteristics of the granulate masscontaining such granules. The pores between particles on the surface ofthe porous granule as shown in FIG. 2 d may enhance the compressibilityof the granule.

FIG. 2 e shows another embodiment of granules of the present invention.Image 250 shows a plurality of 100% paracetamol granules 251 produced bythe apparatus of an embodiment of the invention. Compaction force of 60kN was used in the granulation process. According to our observation,paracetamol may be granulated using higher compaction forces than mostother materials. Unless specified differently, the fractionating deviceused in the process of this and following examples is similar to the onedescribed in FIGS. 4 and 5 c. Typical size of a granule 251 in thissample is between 500 and 1000 μm. Image 252 shows a magnified pictureof the surface of one of such granules. It may be observed from image252 that the compacted surface 254 of the granule is covered mostly bysmall granules 255 (e.g. in the range of ca 5 μm-50 μm). Such individualsmall granules 257 are also shown in image 256. The small granules 255are relatively loosely attached to the granule 251 forming a poroussurface for the granule. Thus, although the compaction force used washigher than with typical materials, the surface of the resultinggranules can be visually observed to be porous. Inventors contemplatethat the small granules and/or fine particles may have been attached tothe larger granules via electrostatic forces created e.g. bytriboelectrification during the fractionating step of the process. Theinventors contemplate further that the porous surface achieved vialoosely attached small granules on the surface of the accepted granulemay have a significant positive contribution to the flow andtabletability properties of the granulate mass.

FIG. 2 f shows yet another embodiment of granules of the presentinvention. Image 260 shows a plurality of excipient granules 261comprising 70% of microcrystalline cellulose and 30% of maize starch. Acompaction force of 16 kN was used in the granulation process. Typicalsize of a granule 261 in this sample is between 500 and 1000 μm. Image262 shows a magnified picture of the surface of one of such granules. Itmay be observed from image 262 that the compacted surface of the granuleis covered by small granules and/or fine particles 263 (e.g. in therange of ca 5 μm-100 μm). Such individual small granules 265 andindividual fine particles 266 are also shown in image 264. Smallgranules 265 and fine particles 266 are relatively loosely attached tothe granule 261 forming a porous surface for the granule. The proportionof small granules (in this example, granules smaller than 106 μm) wasapproximately 20%. The flowability of the mass was observed to beexcellent.

FIG. 2 g illustrates formation of granules from raw material comprising50% microcrystalline cellulose and 50% of maize starch. Image 270 showsa SEM-image of unprocessed raw material. Image 271 shows a SEM-image ofcompacted but not yet fractionated granular mass. Compaction force of 25kN was used in the experiment. Image 272 shows a SEM-image of granularmass accepted by the fractionating device of an embodiment of thepresent invention. The magnification of images 270 and 271 isessentially similar and image 272 has 0.1× magnification in comparisonto images 270 and 271. Image 270 shows practically no granules. In image271, attention is drawn to the relatively small size of the granulesproduced in the compacting step. Granules in the compacted mass 271created by the roller compactor and flake crusher (110 and 111 in FIGS.1 a and 1 b) are generally smaller than 500 μm whereas majority of thegranules 272 accepted by the fractionating device (see FIG. 4) arelarger than 500 μm. This surprising observation makes inventors believethat new acceptable granules may be created and/or granules may furtheragglomerate during the fractionating phase of the method of anembodiment of the present invention.

FIG. 2 h shows particle size distribution charts of materials depictedin images 271 and 272 of FIG. 2 g. According to the productcertification data of raw materials used, the size distribution ofparticles of the raw material (not shown in figures) is such thatpractically all particles of the mass are smaller than 106 μm. When themass is compacted, the proportion of granules of acceptable sizeincreases slightly as shown in image 280 but the majority (approximately73%) of particles are still smaller than 106 μm. Image 281 shows thatafter fractionation, the proportion of granules larger than 106 μmincreases significantly. The accepted fraction still contains about 10%of small granules and/or fine particles smaller than 106 μm. Despite therelatively large proportion of small granules and/or fine particles, themass exhibits excellent flowability. The total proportion of granulesaccepted from the compacted mass in the fractionating step wasapproximately 10%. Thus, approximately 90% of the mass was rejected bythe fractionating device.

FIG. 2 i is explained in the examples section of this document.

FIG. 2 j shows SEM-images of surfaces of granules manufactured usingembodiments of the present invention. Different compaction forces havebeen used in the granulating process. The material shown comprises 50%of microcrystalline cellulose and 50% of maize starch. Images 290, 291,292 depict granules produced using compaction force of kN, 40 kN and 60kN, respectively. Attention is drawn to the decreasing surface porositywhen the compaction force is increased. Numerous pores are easilydetectable in granules of images 290 and 291 whereas there are largedense areas in granule of image 292. Lack of pores on the surface of thegranule may deteriorate at least some of the properties of the granularmass, e.g. flowability of the mass, tablettability of the mass and/ordisintegration time of resulting tablet. Thus it is suggested that theoptimal compaction force for producing granules from this raw materialis probably below 60 kN. Although the SEM images 290, 291 do not showsignificant differences in the structure of the surface of the granule,the granular mass produced using compaction force of 25 kN form tabletswith higher tensile strength and quicker disintegration time than themass produced with compaction force of 40 kN.

An exemplary fractionating device that may be suitable for use in thepresent apparatus is shown in FIG. 3 a. The device 300 made of stainlesssteel comprises an aperture of input material 301 through which thepowder 306 comprising at least some granules e.g. larger than 150 μm islead to the device. In addition to the granules, the input materialtypically comprises a substantial proportion of fine particles and/orgranules e.g. smaller than 150 μm. The powder falls e.g. by effect ofgravitation into the device that comprises an open-ended cone 304 and anoptional cylindrical section 305. In other embodiments, also othershapes different than a cone may be used as long as the shape enablescreation of at least one, advantageously downward narrowing, verticalvortex. The input material travels in the device along a helical path ofthe vortex.

The passage of powder into the device 300 may be controlled e.g. using apair of valves (not shown in figure), e.g. a pair of star-shaped flapvalves. The same controlling means may also be used for blocking flow ofreplacement air through the aperture of input material 301. In oneexemplary embodiment, the height of the cone is 200 mm, the height ofthe cylinder is 100 mm, the diameter of the cylinder 305 is 170 mm, thediameter of the aperture of the accepted material 303 is 50 mm and theinner diameter of the carrier gas outlet tube 302 is 40 mm. In thisembodiment, an inner cylinder 310 is partially (e.g. 80 mm in theembodiment described here) inside the cylindrical component 305. Thediameter of the inner cylinder in this embodiment is 90 mm. Flow of anysignificant volume of replacement air through the inner cylinder 310 isessentially blocked. In different embodiments, also differentmeasurements may be used.

The carrier gas outlet tube 302 is suitably arranged so that it causes avortex inside the device 300. Replacement carrier gas 308 is led intothe device through the aperture of the accepted material 303. Forexample, the tube may be attached tangentially to the cylindricalsection 305. The inventors have made a surprising observation that whena vortex is induced inside the vertically positioned device by suckingcarrier gas through tube 302, the device produces acceptable granules307 and fractionates unacceptable material quite efficiently. Theacceptable granules fall downwards in the vortex by effect ofgravitation whereas the fine particles and small granules are entrainedby the gas stream sucked out of the device through aperture 302. Someproportion (e.g. up to 20, 40, 60 or 80%) of acceptable granules mayalso be sucked out of the device through the tube 302. During theirresidence in the device, fine particles and/or small granules mayagglomerate with other granules, thus making the granules grow further.

At least with some materials, the resulting granules have been observedto have high charge of static electricity. When necessary, afractionating device may also comprise means 311, e.g. a vibrating or anultrasound emitting device for preventing buildup of material in variousstructures of the device.

In an alternative embodiment to that shown in FIG. 3 a, the cylindricalupper section of the device could be omitted and the carrier gas outtube 302 could be attached to the frustoconical section 304.

FIG. 3 b depicts operating principle of another fractionating devicethat according to inventors' contemplation may be applicable in someembodiments of the present invention. The device 320 comprises acylinder 321 that may be e.g. vertically oriented. An inner cylinder 322is attached to the cylinder 321. Input material 324 falls to the devicethrough the inner cylinder against the gas stream 325. The gas stream iseffected by sucking carrier gas through the tube 328. While falling inthe cylinder 321, fine particles and/or small granules are entrained inthe gas stream. The acceptable granules 326 fall out of the cylinder andrejected fraction 327 is sucked out of the device through tube 328.Although the embodiment shows only one tube 328, any suitable way ofarranging the suction of carrier gas may be used. Suitably, the tube(s)328 is (are) attached to the device at least partially above the levelof the bottom of the inner cylinder 322. It is noteworthy to observethat in this embodiment, carrier gas does not necessarily form anyvortex and powder material does not thus follow a helical path insidethe device. The possible fractionating effect may thus be achieved atleast partially using turbulent gas flow.

FIG. 3 c illustrates yet another fractionating device that, according tocontemplation of the inventors, may be applicable for use in someembodiments of the method and apparatus of the present invention. Thematerial comprising at least some granules e.g. larger than 150 μm fallsinto the fractionating device through an aperture of input material 331.The feed of material to the device may be controlled using at least onevalve that may also block flow of gas through the aperture 331. Inaddition to the granules, the input material typically comprises asubstantial proportion, e.g. at least 25%, of fine particles and/orgranules e.g. smaller than 150 μm. The powder falls e.g. by effect ofgravitation into the device that comprises a belt conveyor that conveysthe material against gravitation in an elevation angle 332. The angle ischosen so that the acceptable fraction of the material falling onto thebelt 338 may flow downwards towards the aperture of accepted material337 against the belt movement 333. The belt movement may be achievede.g. by rollers 334 a, 334 b and 334 c. A gas stream 336 may be arrangedto flow above the conveyor belt 338. Conveniently, replacement gas isled into the device through the aperture of accepted material 337.Material that is able to flow downwards on the belt against the movementof belt and against the gas flow towards the aperture 337 may compriseacceptable granules. The rejectable material that does not properly flowdownwards against the conveyor 338 movement 333 and the gas stream 336is conveyed away from the device by the gas stream 336 and/or by theconveyor through aperture 339 of rejected material. The movement of atleast the downward flowing acceptable granules on the belt may have aspinning component. The spinning of the individual acceptable granulesmay contribute to the separation of fine particles and/or small granulesfrom the acceptable granules.

The device may also comprise conveyor (belt) cleaning means 335 a and335 b. Advantageously, to keep the material flows and gas stream insidea closed device, the belt conveyor is enclosed in a closed chambercomprising an aperture for input material, accepted granules andrejected granules.

This embodiment illustrates how the flowability of the material maycontribute to the fractionation of the material. The fraction of thematerial that flows well, flows downwards (at an angle 332) bygravitation on the conveyor belt whereas the fraction of the materialthat does not flow properly, is entrained in gas stream and/or isconveyed out of the device using a conveyor.

FIG. 4 illustrates an example of an enhanced fractionating device. Inthe figure, components and structures residing inside the device aredrawn using dotted lines. The device 400 comprises a fractionatingchamber and, mounted inside the chamber, an open ended cylinder (orcone-shaped device, not illustrated) 401 rotatably supported on rollers410. The rotating speed of the cylinder can be adjusted to be forexample the maximum available in the device of make ROTAB™ (DonsmarkProcess Technology A/S, Frederiksberg, Denmark) and model 400EC/200. Thejacket of the cylinder or cone may be perforated. There are norestrictions with regard to the number and shape of the possibleapertures or their edges except for that the apertures should beconstructed so that the gas (air) together with entrained fine particlesis able to leave the cylinder through them. The apertures may be, forinstance, round, oval or slots. In one embodiment, the apertures areround and they have been cut using laser cutting techniques. In oneembodiment, the diameter of the round apertures is 1.5 mm. A drive motor402 is arranged to rotate the cylinder at a suitable speed, e.g. at 100RPM. A spiral structure 403 is provided inside the cylinder fortransporting the solid material from the feed end 411 to the outlet 404as the cylinder rotates. Instead of a spiral, various kinds of fins orother structures can be provided internally within the cylinder toobtain movement of the compacted material, and its interaction with thegas stream. The angle of inclination of the cylinder may be adjusted asrequired by, for instance, changing the position of the wholefractionating device 400 in its suspension structure 413, 414.

The powder 405 leaving the compacting device falls through a chargeconnection 412 into the feed end 411 of the cylinder and is transportedby the spiral 403 towards an outlet tube 404. The carrier gas 406flowing through the outlet 404 moves in the opposite direction to theaccepted granules 407. Acceptable granules pass along in the cylinder401, and fall through the outlet 404 to a product container (not shown)by effect of gravitation. Unacceptable fine particles and/or smallgranules that may be accompanying the acceptable granules to the tube404 are generally conveyed back from the tube 404 to the cylinder 401 bythe gas stream 406. In the present device, the outlet 404 is a downwardpointing tube whose length is 70 mm and diameter is 40 mm. The rejectedfraction of fine particles and/or small granules 408 together with thecarrier gas stream flows to the feeding conveyor (see 102 in FIG. 1),through connection 409 for reprocessing. The granules may grow in sizein the fractionating device 400 (or 300 in FIG. 3 a). This agglomerationmay be caused e.g. by triboelectrification and electrostatic forces. Asin the embodiment shown e.g. in FIG. 3 c, the movement of individualaccepted granules in the rotating cylinder may have a spinning componentcaused by the flow of material against the wall of the rotatingcylinder. This may contribute to the fractionation effect of the device.

It is also noteworthy to observe that the cylinder 401 may act not onlyas a fractionating means but also as a buffer and conveyor of inputmaterial. Thus, this embodiment may provide benefits over the otherfractionating means described herein. One such benefit is for examplethe ability to absorb bursts of input material 405 coming from thecompacting device.

The embodiment shown in FIG. 4 comprises also means 416 for keeping therotating cylinder clean. One such means blows pressurized gas (e.g. air)through a plurality of holes towards the cylinder 401. The pressure usedmay be e.g. 1-4 bar.

The fractionating means may also comprise means 417 for monitoring theprogress of material in the fractionating device. Such means may be e.g.a sensor measuring the rotating speed of the cylinder or any othersuitable means known to a person skilled in the art.

The properties of the accepted fraction may be influenced e.g. bychanging the rotation speed of the cylinder, the angle of inclination ofthe cylinder, the pitch of the spiral, and the size, number and locationand the shape of the apertures in the cylinder as well as by varying theflow rate of the carrier gas.

FIGS. 5 a and 5 b show two different forms of the cylinder-shaped deviceresiding inside the fractionating device (see 400 in FIG. 4). A cylinder500 has apertures 501 that in the FIG. 5 a are situated throughout thejacket of the cylinder whereas in FIG. 5 b there are apertures only inone end of the cylinder. The input material 502 that contains bothgranules and fine particles is fed to the rotating cylinder from one endof the cylinder. The rotating movement 503 of the cylinder 500 and thespiral (see 403 in FIG. 4) inside the cylinder push the input materialtowards the other end of the cylinder. While the material is moving inthe cylinder, carrier gas flow 504 separates the acceptable granulesfrom the rejected fine particles and/or small granules 505 which areconveyed out of the cylinder through apertures 501 with the carrier gasflow. The accepted granules 506 are eventually pushed out of thecylinder by the spiral structure that resides inside the cylinder.

In the shown embodiment, the rotating device is a cylinder of diameterof 190 mm and length of 516 mm and comprises apertures each having adiameter of 1.5 mm and the apertures reside on average 6 mm from eachother. The air stream that enters the fractionating device throughaperture 404 (FIG. 4) is further led out of the fractioning chamber forreprocessing through an aperture (409 in FIG. 4) of 50 mm in diameter.Inside the cylinder there is a screw-shaped guiding structure thatadvances 80 mm per revolution towards the aperture of accepted material506. The height of the guiding structure is 25 millimeters. FIG. 5 cshows a drawing of an exemplary perforated 511 stainless steel sheet 510that may be used to build a suitable cylinder. The thickness of thesheet is about 0.8 mm. In this example sheet, dimension 512 a is 51 cm,dimensions 512 b and 512 c are 8 cm, dimensions 512 d and 512 e are 1 cmand dimension 512 f is 48 cm. The ROTAB™ device described above has beenmodified by changing the cylinder to one assembled from the steel sheetof FIG. 5 c and the fractionating chamber has been changed to one havingthe shape similar to one shown in 400 of FIG. 4.

Although the devices shown in FIGS. 5 a and 5 b are open-ended andcylinder shaped, and the movement involved is a rotating movement,conveyor devices of other shapes and utilizing other kinds of movementsmay also be used to convey the mass in the fractionating air stream.

The device may optionally be adapted to improve its continuousprocessing capabilities. One such adaptation is disclosed in FIG. 6where a dual filter assembly is illustrated. The majority of fineparticles and/or small granules is separated from carrier gas, e.g. air,in cyclone 602 (see also 106 in FIG. 1 a or 1 b), but some fineparticles and/or small granules may be sucked out of the cyclone withthe carrier gas. Those particles may need to be filtered out before thecarrier gas leaves the system. The filters 607 a, 607 b collect the fineparticles and/or small granules until the filter is cleaned. One filter607 a, 607 b may be active while the other is being cleaned e.g. byvibrating it. The valves 605, 612 may be used for guiding the gas flowthrough the active filter and for isolating the filter being cleanedfrom the gas stream. The powder resulting from the filter cleaning fallsbelow the filter and further to a tube 609 a, 609 b when the valve 608a, 608 b respectively is opened. In the other end of the tube, there maybe a lower valve 610 a, 610 b that is opened after the upper valve 608a, 608 b has been closed. Opening the lower valve causes the powder tofall back into the circulation for re-processing. This arrangement makesit possible to clean one of the filters while the apparatus isoperational and the cleaning operation doesn't result in undesirablepressure shocks of carrier gas in the apparatus.

The apparatus may also optionally be equipped for example with sensorsthat measure e.g. the output rate of accepted material and/or size ofaccepted granules in real-time. An example about such an arrangement isshown in FIG. 7. Accepted granules leave the fractionating device 700through tube 701. Light emitting devices 702 as well as light sensitivesensors 703 have been installed in the tube to observe the size of thepassing accepted granules. Based on the information created by thesensors, the control logic of the system may adjust the operatingparameters of the apparatus. One such adjustable parameter may be forexample the size of granules produced by the flake crushing screen 704.Another such adjustable parameter may be the gas flow rate of thesystem. Yet further adjustable parameter is operation of any of thevalves of the arrangement.

It may also be possible to equip the arrangement with a bulk flowabilityanalyzer device that collects samples of accepted granules and teststheir flowability, using e.g. a funnel illustrated in FIG. 9. Anyoperating parameter, e.g. gas flow rate, compaction force or rotatingspeed of the cylinder of the fractionating means may be adjusted if theaccepted granules do not pass the flowability test.

FIG. 8 illustrates an exemplary optional arrangement for granulatingpowders separately and then mixing the granules together. Theproperties, e.g. disintegration time, of the end product, e.g. tablet,may be affected by granulating components of a formulation in multiplegranulation processes vs. together in one process.

Granulation systems 801, 802 each produce granules from differentsubstances (or from the same substance but with different granulationparameters such as compaction force or size of accepted granules). Eachsystem has its own means 811, 812 of adjusting the granulationparameters. The accepted granules from each granulation system are ledthrough a conveyor 803, 804 to a granule mixing device that has means806, 807 to control the amount of each of the granules in the final mix.The mixing device may also have granule mixing means 808 to mix thegranules together before the granulate mass flows to the container offinal product 810 or directly to a tableting machine (not shown). Theconveyor 803, 804 in FIG. 8 is a tube that leads to the mixing device,but the conveyor may also lead the granules into an intermediary storagecontainer from which the mass may conveyed to the mixing device.

FIG. 9 illustrates a simple device for measuring flowability of powderor granulate mass. Devices of different sizes are used for determiningdifferent degrees of flowability. The degree of flowability may besufficient, good, very good or excellent.

The device for determining sufficient flowability has a smooth plasticsurface cone 900 with a height 901 of 45 millimeters and with cone angle902 of approximately 59 degrees and a round aperture 903 whose diameteris 12 millimeters. The length of tube 904 is 23 mm. In a flowabilitytest procedure, the cone is filled with powder or granulate mass whilethe round aperture 903 is kept closed. The aperture is opened, cone isknocked lightly to start the flow and the flow of the powder through theaperture by mere gravitation force is observed. Additional shaking orother kind of movement of the cone during the test is not allowed. Thematerial passes the flowability test if the cone substantially empties.“Substantial” here means that at least 85%, 90% or 95% of the powderleaves the cone.

The device for determining good flowability using the test procedureexplained above has a smooth glass surface cone 900 with a height 901 of50 millimeters and with cone diameter 905 of 70 mm and a round aperture903 whose diameter is 7 millimeters. The length of tube 904 is 70 mm.

The device for determining very good flowability has a smooth plasticsurface cone 900 with a height 901 of 35 millimeters and with conediameter 905 of 48 mm and a round aperture 903 whose diameter is 4millimeters. The length of tube 904 is 50 mm.

The device for determining excellent flowability has a smooth plasticsurface cone 900 with a height 901 of 40 millimeters and with conediameter 905 of 55 mm and a round aperture 903 whose diameter is 3millimeters. The length of tube 904 is 60 mm.

Using the above mentioned or other embodiments of the present invention,it is possible to produce granules that have one or multiple of somedesirable general characteristics, e.g. good flowability, goodcompressibility, good tabletability, quick disintegration time of atablet and high drug load. We have observed that those characteristicsare applicable to many APIs and excipients. Thus, some potentiallytime-consuming and expensive parts of the drug formulation designprocess of prior art may be avoided with many APIs. The embodimentsshown are also relatively cost-efficient to build and use. For example,it is possible to build an arrangement that is capable of producingseveral kilograms or tens of kilograms of granules per hour. The processis also relatively simple and easy to control in comparison to e.g. wetgranulation methods of prior art. In the shown embodiments, there arefew parameters that may need to be adjusted.

Further aspects of the invention are defined by the following clauses:

-   1) A granulate mass, characterized in that the mass is tabletable    and has good flowability and that the mass comprises at least 10% of    at least one of the following pharmaceutical ingredients:    -   acebutolol HCl,    -   fluoxetine HCl,    -   paracetamol,    -   sodium valproate,    -   ketoprofen and    -   metformin HCl.-   2) A tablet, characterized in that the tensile strength of the    tablet is at least 10N and the tablet is manufactured from    thy-granulated granules comprising at least 10% of at least one of    the following active pharmaceutical ingredients:    -   acebutolol HCl,    -   fluoxetine HCl,    -   paracetamol,    -   sodium valproate,    -   ketoprofen, and    -   metformin HCl.-   3) A tablet, characterized in that the tablet exhibits substantially    low percentage of liquid and/or hydrogen bonds, lubricant is    unevenly distributed across the tablet and the tablet has further at    least two of the following properties: quick disintegration time,    high tensile strength, high drug load and low amount of lubricant.-   4) A tablet formed by compression of a dry granulate mass comprising    60% or more of active pharmaceutical ingredient selected from    paracetamol, metformin HCl, acebutolol HCl and sodium valproate.-   5) A tablet according to clause 4) which disintegrates in water of    approximately body temperature in less than 60 seconds.-   6) A tablet according to clauses 4) or 5) which contains active    pharmaceutical ingredient in an amount does not exceed 95% and    wherein the composition contains at least 2% of disintegrant.-   7) A tablet according to any one of clauses 3) to 6) which comprises    xylitol in an amount of 90% or less.

Percentage (%) values given herein are by weight unless otherwisestated.

Mean values are geometric mean values unless otherwise stated. Meanvalues of particle size are based on weight.

The examples below describe characteristics of some typical granules andtablets achievable using the embodiments of the present invention.

Examples

To observe the characteristics of the granulate mass of variousembodiments of the invention and their tabletability, a series of testshas been conducted. In all tests, method and apparatus described in thisdocument (e.g. FIG. 1 b and FIG. 4) has been used. The gas flow rate ofthe apparatus was adjusted so that the fractionating effect of the gasflow resulted in a granulate mass that had good, very good or excellentflowability. The gas flow rate in the tests was achieved operating thesuction fan (BUSCH™ Mink MM 1202 AV) of the system at a default speed ofapproximately 1860 RPM. With some materials, the speed was altered fromthe default to achieve desired quality of the granulate mass. Thecompaction force of the roller compactor was adjusted to producegranules with optimal tableting characteristics. The force used wasrecorded as kilonewtons as indicated by the roller compactor (HOSOKAWABepex Pharmapaktor L200/50P) used in the tests. The diameter of therolls of the compactor is 200 mm and the working width of the rolls is50 mm. The thickness of the ribbon produced by the compactor is about 4mm. The rotating speed of the rolls is typically between 10 and 12 RPM.The exact rotating speed is adjusted by the roller compactor to achievethe desired compaction force. The default mesh size of the flakecrushing screen is 1.00 mm. In some experiments, the mesh size of theflake crushing screen was altered from the default.

Unless specified differently, a rotating device as shown in FIG. 4operating at about 100 RPM was used as the fractionating means of theapparatus of the tests. The default size of apertures in the cylinder ofthe rotating means was 1.5 mm.

In all tableting tests, 0.25% of magnesium stearate was added to thegranulate mass prior to tableting as a lubricant.

Maize starch used in the tests was estimated to have particle sizebetween 5 and 30 μm.

The tensile strength of the tablets has been measured using a measuringdevice of make MECMESIN™ (Mecmesin Limited, West Sussex, UK) and modelBFG200N.

The particle size distribution of granulate mass was measured usingstack of sieves. In the measurements, the stack of four sieves wasshaken for 5 minutes using an Electromagnetic Sieve Shaker(manufacturer: C.I.S.A Cedaceria Industrial, S.L, model: RP 08) withpower setting 6. The opening sizes of the sieves used were 850 μm, 500μm, 250 μm and 106 μm.

Tableting Example 1 90% Acebutolol HCl

A powder mass of 5.0 kg having 90% of acebutolol HCl powder (meanparticle size 27 μm) and 10% of starch was mixed. Compaction force of 40kN was used to compact mass into granules having mean size of 877 μm andstandard deviation of 1.421 after fractionation. The loose bulk densityof the resulting mass was 0.68 g/ml and the mass had good flowability.Round tablets of 10 mm diameter and 500 mg of weight were created usingtableting force of 6-8 kN. The average tensile strength of the tabletwas 80N (N=10). Tablet disintegration time was observed to be about 6.5minutes in water of approximately body temperature.

Tableting Example 2 20% Fluoxetine HCl

A powder mass having 20% (2.24 kg) of Fluoxetine HCl (Manufacturer:SIFAVITOR SpA, Casaletto Lodigiano. Italy. Batch no. 2700/01/06), 64%(7.168 kg) of microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6,batch 5S3682) and 16% (1.792 kg) of maize starch (CERESTAR Mat. no.03401 batch 01015757) was mixed. Compaction force of 35 kN was used tocompact mass into granules having mean size of 461 μm and standarddeviation of 2.358 after fractionation. The mesh size of the flakecrushing screen was set to 1.25 mm. The loose bulk density of theresulting mass was 0.595 g/ml and the mass had good flowability. Roundtablets of 6 mm diameter and 112 mg of average weight (N=10, standarddeviation=1.89%) were created using maximum tableting force thatproduced no capping. The average tensile strength of the tablet was 44 N(N=10, standard deviation=11.17%). Tablet disintegration time wasobserved to be about 10 seconds in water of approximately bodytemperature.

Tableting Example 3 60% Paracetamol

A powder mass of approximately 4.0 kg having 60% of paracetamol finepowder (Manufacturer: Mallinckrodt Inc.—Raleigh (USA)—Batch 7845906C563,59% of particles smaller than 20 μm, 96% of particles smaller than 75μm), 20% of microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6, batch5S3689, 50% of particles smaller than 71 μm) and 20% of maize starch(CERESTAR Mat. no. 03401, batch 01015757) was mixed. Compaction force of30 kN was used to compact the mass into granules having mean size of 645μm and standard deviation of 1.464 after fractionation. The mesh size ofthe flake crushing screen was set to 1.00 mm. The bulk density of theresulting mass was 0.586 g/ml and the mass had good flowability. Roundconvex tablets of 10 mm diameter and 454 mg of average weight (N=10,standard deviation=0.6%) were created using maximum tableting force thatproduced no capping. This was a very good result since hitherto it hasbeen considered difficult, if not impossible, to produce high loadtablets of paracetamol by compression of granulates prepared using drygranulation methods. The average tensile strength of the tablet was 49 N(N=10, standard deviation=12.73%). Tablet disintegration time wasobserved to be less than a minute in water of approximately bodytemperature.

Tableting Example 4 50% Ketoprofen

A powder mass of approximately 8.0 kg having 50% of ketoprofen(Manufacturer: Ketoprofen S.I.M.S. Societa italiana medicinaliScandicci, batch 121.087, 79% or particles smaller than 60 μm) and 50%of maize starch (CERESTAR Mat. no. 03401, batch SB4944) was mixed.Compaction force of 40 kN was used to compact the mass into granuleshaving mean size of 900 μm and standard deviation of 1.418. The meshsize of the flake crushing screen was set to 1.00 mm. The loose bulkdensity of the resulting mass was 0.625 g/ml and the mass had goodflowability. Round convex tablets of 6 mm diameter and 94 mg of averageweight (N=10, standard deviation=1.94%) were created using maximumtableting force that produced no capping. The average tensile strengthof the tablet was 39 N (N=10, standard deviation=14.56%). Tabletdisintegration time was observed to be about 10 seconds in water ofapproximately body temperature.

Tableting Example 5 80% Metformin HCl

Approximately 4.0 kg of powder mass having 100% of metformin HCl(Supplier: SIMS trading (Firenze, Italy), batch 21.039) was compactedusing compaction force of 35 kN to produce granules having mean size of668 μm and standard deviation of 1.554. The mesh size of the flakecrushing screen was set to 1.00 mm. The loose bulk density of theresulting mass was 0.694 g/ml and the mass had good flowability.Separately, excipient granules containing 70% of microcrystallinecellulose (EMCOCEL CAS No. 9004-34-6, batch 5S3689) and 30% of maizestarch (CERESTAR Mat. no. 03401, batch 01015757) was mixed andgranulated using the same compaction force. Then 80% of metformingranules were mixed with 20% of excipient granules and compressed intotablets. Round convex tablets of 12 mm diameter and containing 500 mg ofmetformin were created using maximum tableting force that produced nocapping. The average tensile strength of the tablet was 59 N (N=3).Tablet disintegration time was not measured.

In addition to tableting examples, compressibility and flowability ofgranulate mass of embodiments of the invention was tested by measuringthe Hausner ratio of the mass and observing the flowability of the mass.Methods usable for calculating Hausner ratio and observing flowabilityof the mass have been described earlier in this disclosure.

Flowability Example 1 100% Paracetamol

A powder mass of 4.0 kg having 100% paracetamol (Manufacturer:Mallinckrodt Inc.—Raleigh (USA)—Batch 6088906C107) was compacted usingcompaction force of 12 kN and flake crushing screen mesh size of 1.00 mminto granules having mean size of 708 μm and standard deviation of 1.349after fractionation. 0.58% of the granules of the mass had diameter ofsmaller than 106 μm. The bulk density of the resulting mass was 0.610g/ml and tapped bulk density was 0.758 g/ml. The Hausner ratio of themass was calculated to be 1.24. Despite the relatively highcompressibility as indicated by the Hausner ratio, the flowability ofthe mass was observed to be excellent.

Flowability Example 2 90% Metformin HCl

A powder mass having 90% (4.0 kg) of Metformin (METFORMIN HYDROCHLORIDEUSP, BATCH N. 17003742, USV LIMITED, B.S.D. Marg. Govandi, Mumbay 400088, INDIA), 8% (356 g) of microcrystalline cellulose (EMCOCEL CAS No.9004-34-6 Batch 5S3682) and 2% (88 g) of maize starch (CERESTAR Mat. no.03401, batch 01015757) was mixed. Compaction force of 30 kN, flakecrushing screen mesh size of 1.00 mm and suction fan speed of 2100 RPMwas used to produce granules having mean size of 477 and standarddeviation of 2.030 after fractionation. 11.0% of the granules of themass had diameter of smaller than 106 μm. The loose bulk density of theresulting mass was 0.581 g/ml and tapped bulk density was 0.714 g/ml.The Hausner ratio of the mass was measured to be 1.23. Despite therelatively high compressibility as indicated by the Hausner ratio, theflowability of the mass was observed to be excellent. When experimentingwith metformin, the inventors have also made a surprising observationthat although 100% metformin fine powder exhibits heavy agglomeration(forming large, hard agglomerates) when stored in room temperature andambient humidity, 100% metformin granules made of such powder using amethod of the invention show practically no such agglomeration duringstorage time.

Flowability Example 3 Excipient

A powder mass of approximately 3.0 kg containing 70% of microcrystallinecellulose (EMCOCEL CAS No. 9004-34-6 Batch 5S3689) and 30% of maizestarch (CERESTAR Mat. no. 03401, batch 01015757) was mixed. Compactionforce of 16 kN and flake crushing screen mesh size of 1.00 mm was usedto produce granules having mean size of 318 μm and standard deviation of2.159 after fractionation. 19.6% of the granules of the mass haddiameter of smaller than 106 ™. The loose bulk density of the resultingmass was 0.379 g/ml and tapped bulk density was 0.510 g/ml. The Hausnerratio of the mass was measured to be 1.35. Despite the highcompressibility of the mass as indicated by the Hausner ratio, theflowability was observed to be excellent.

Flowability Example 4 20% Ketoprofen

A powder mass of approximately 4.0 kg containing 20% of ketoprofen(S.I.M.S. Society italiana medicinali Scandicci, batch 121.087) and 80%of microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6 Batch 5S3689)was mixed. Compaction force of 24 kN and flake crushing screen mesh sizeof 0.71 mm was used to produce granules. When the suction fan speed ofthe system was set at 1980 RPM, the mean size of the accepted granuleswas 304 ™ and standard deviation was 2.275 after fractionation. 23.0% ofthe mass had particle size smaller than 106 μm. The loose bulk densityof the mass was 0.510 g/ml and tapped bulk density was 0.676 g/ml. TheHausner ratio of the mass was measured to be 1.325. The flowability ofthe mass was observed to be sufficient. When the suction fan speed ofthe system was set at 2400 RPM, the mean size of the accepted granuleswas 357 μm and standard deviation was 2.121 after fractionation. 13.7%of the mass had particle size smaller than 106 μm. The loose bulkdensity of the mass was 0.521 g/ml and tapped bulk density was 0.714g/ml. The Hausner ratio of the mass was measured to be 1.371. Theflowability of the mass was observed to be excellent. This example showsthat by varying the gas flow rate of the system, granulate mass withdifferent flow characteristics may be obtained. This example alsoindicates that, contrary to what is taught in prior art, e.g. U.S. Pat.No. 6,752,939, the Hausner ratio doesn't necessarily predict theflowability of the granulate mass. For example, the granule sizedistribution of the granular mass may have greater effect on flowabilitythan the compressibility of the granulate mass. Good compressibility andflowability may thus co-exist in the same granulate mass.

Capacity Example

The embodiments described in this disclosure are capable of producingsignificant amounts of granulate mass. In a capacity test of oneembodiment comprising the fractionating device of FIG. 4, 5.98 kg ofParacetamol (7845 Paracetamol Fine Powder—Mallinckrodt Inc.—Raleigh(USA)—Batch 7845906C563), 10.69 kg of Microcrystalline Cellulose (CASno. 9004-34-6—JRS PHARMA LP—Patterson (USA)—Batch 5S3689), 37.10 kg ofmaize starch (CERESTAR Mat. n. 03401 Batch 01015757), 12.19 kg oflactose (LACTOSE MONOHYDRATE—DMV International Pharmatose 80M DP5500Batch 10209285 906535704), 34.04 kg of cellulose (“Technocel”—CFFGmbH—Gehren Germany—Batch G13060620) were mixed and granulated usingcompaction force of ca. 40 kN and suction fan speed of 2160 RPM. Theapparatus was running for two hours and 38 minutes producing 94.66 kg ofgranules which had at least good flowability characteristics.

Fractionating Example 1

A powder mass of approximately 5.0 kg containing 50% of microcrystallinecellulose (EMCOCEL CAS No. 9004-34-6 Batch 5S3689) and 50% of maizestarch (CERESTAR Mat. no. 03401, batch 01015757) was mixed andgranulated. Reprocessing of the rejected fraction was prevented in thegranulation process. To achieve this, the mass to be processed wasmanually fed to the intermediate vessel (107 in FIG. 1 b) from where itwas conveyed to the compactor (110 in FIG. 1 b) by opening the valve(109 a and 109 b in FIG. 1 b) before starting the process. The processwas then started and the mass of 5.0 kg was granulated and fractionated.During the processing, the valves (109 a and 109 b in FIG. 1 b) was keptshut to prevent re-processing of the rejected fraction. Compaction forceof 40 kN and flake crushing screen mesh size of 1.00 mm was used toproduce granules having mean size of 523 μm (standard deviation 1.70)after fractionation. The test run produced 1630 g (32.6%) of acceptedgranules. A SEM image of the surface of an accepted granule is shown inimage 291 of FIG. 2 j. The rest of the mass was rejected by thefractionating device. 4.0% of the granules/particles of the acceptedmass had diameter of smaller than 106 μm. The loose bulk density of theresulting mass was 0.56 g/ml and tapped bulk density was 0.641 g/ml. TheHausner ratio of the mass was measured to be 1.15. The flowability ofthe accepted fraction was observed to be excellent. On the other hand,the flowability of the rejected fraction was observed to beinsufficient.

The rejected fraction contained 16.4% of granules larger than 250 μmwhereas the accepted fraction contained 92% of granules larger than 250μm.

To observe the tabletability of the accepted fraction of the granulatemass, 0.5% of magnesium stearate was added to the mass and tablets ofaverage weight of 588 mg were produced. The average tensile strength ofthe tablet (N=6) was measured to be 23.56N and standard deviation was1,308. The disintegration time of the tablet was observed to be about 12seconds.

Fractionating Example 2

Unlike in the above examples, a fractionating device according to theembodiments of FIGS. 1 a and 3 a of this disclosure was used in thefractionating step of the granulating process. The mass to be processedcomprised 80% of microcrystalline cellulose (CAS no. 9004-34-6—JRSPHARMA LP—Patterson (USA) EMCOCEL 50M—Batch 5S3689) and 20% of maizestarch (CARGILL Mat. n. 03401 Era 01119935). Compaction force of 30 kNwas used to form granules from the mass. As shown in diagram 282 of FIG.2 i, the mass contains more than 60% of particles smaller than 106 μm.After fractionation, the mass contains approximately 11% of particlessmaller than 106 μm. The mass of diagram 282 had poor flowability.Although there still are some fine particles and/or small granules inthe mass of diagram 283, the fractionated mass has very goodflowability. The mass also exhibits good tableting characteristics.

To a person skilled in the art, the foregoing exemplary embodimentsillustrate the model presented in this application whereby it ispossible to design different methods, systems, granules and tablets,which in obvious ways utilize the inventive idea presented in thisapplication.

1. A method for producing granules from a powder, characterized in that a compaction force is applied to the powder to produce a compacted mass comprising a mixture of fine particles and granules and separating and removing fine particles and/or small granules from the granules by entraining the fine particles and/or small granules in a gas stream wherein the fine particles and/or small granules are separated and removed from the granules by means of an apparatus comprising fractionating means which comprises a vortex device in which the compacted mass follows a helical path through the device due to creation of a vortex.
 2. A method according to claim 1 wherein the mean particle size of the powder is less than Y μm and the compaction force is sufficiently low that 75% or less by weight of the powder is compacted into acceptable granules having particle size larger than 1.5×Y μm and at least 150 μm and the rest remains as fine particles and/or small granules.
 3. A method according to claim 1 wherein the compression force is such that the bulk volume of the powder is reduced by 7 to 40% following compaction.
 4. A method according to claim 1 wherein the compaction force is applied by a roller compactor and the compaction force is such that the ribbon produced by the roller compactor has a tensile strength of 40N to 250N when the thickness of the ribbon is about 4 mm.
 5. A method according to claim 1 wherein the compaction force is applied to the powder by a process comprising use of a roller compactor to generate a ribbon of compacted powder which is broken up to produce granules.
 6. A method according to claim 1 wherein the direction of the flow of the gas stream has a component which is contrary to that of the direction of flow of the compacted mass.
 7. A method according to claim 1, characterized in that said compacted mass is moved in said gas stream by effect of gravitation.
 8. A method according to claim 1 wherein the fractionating means does not require passage of the said compacted mass through any sieve.
 9. A method according to claim 1 wherein the residence time of the compacted mass within the fractionating means is at least 2 seconds.
 10. A method according to claim 1 wherein the length of the helical path is at least twice the linear length of travel of the compacted mass along the axis of the device.
 11. A method according to claim 1 wherein the vortex device has a frustoconical lower section and optionally a cylindrical upper section and has a first orifice at the top of the device for entry of material from the compactor, a second orifice at the apex of the frustoconical section for exit of accepted granules as well as entry of carrier gas and a third orifice for exit of carrier gas orientated tangentially to the perimeter of the device and above the first orifice whereby the compacted powder enters the device through the first orifice and passes through the device under the influence of gravitation and the carrier gas enters and exits the device through the second and third orifices respectively causing a vortex effect to be created within the device.
 12. A method according to claim 1, characterized in that said powder comprises an excipient usable in pharmaceutical products and/or an active pharmaceutical ingredient.
 13. A method according to claim 1 wherein the gas of the gas stream contains a reduced proportion of oxygen relative to air.
 14. An apparatus for dry granulation, characterized in that the apparatus comprises compacting means capable of producing compaction force which when applied to a powder produces a compacted mass comprising a mixture of fine particles and granules and fractionating means adapted to separate and remove fine particles and/or small granules from the granules by entraining the fine particles and/or small granules in a gas stream wherein said fractionating means comprises a vortex device in which the compacted mass follows a helical path through the device due to creation of a vortex.
 15. An apparatus according to claim 14 wherein the compaction force is applied by a roller compactor and the compaction force is such that the ribbon produced by the roller compactor has a tensile strength of 40N to 250N when the thickness of the ribbon is about 4 mm.
 16. An apparatus according to claim 14 wherein the direction of the flow of the gas stream has a component which is contrary to that of the direction of flow of the compacted mass.
 17. An apparatus according to claim 14 wherein the fractionating means does not require passage of the said compacted mass through any sieve.
 18. An apparatus according to claim 14 wherein the length of the helical path is at least twice the linear length of travel of the compacted mass along the axis of the device.
 19. An apparatus according to claim 14 wherein the vortex device has a frustoconical lower section and optionally a cylindrical upper section and has a first orifice at the top of the device for entry of material from the compactor, a second orifice at the apex of the frustoconical section for exit of accepted granules as well as entry of carrier gas and a third orifice for exit of carrier gas orientated tangentially to the perimeter of the device and above the first orifice whereby, in use, the compacted powder enters the device through the first orifice and passes through the device under the influence of gravitation and the carrier gas enters and exits the device through the second and third orifices respectively causing a vortex effect to be created within the device.
 20. A method for preparing a tablet which comprises producing granules by a method according to claim 12 thereby to produce a dry granulate mass and compressing said dry granulate mass optionally blended with one or more additional excipients thereby to produce a tablet. 